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Le Maître M, Guerrier T, Sanges S, Chepy A, Collet A, Launay D. Beyond circulating B cells: Characteristics and role of tissue-infiltrating B cells in systemic sclerosis. Autoimmun Rev 2025; 24:103782. [PMID: 40010623 DOI: 10.1016/j.autrev.2025.103782] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 02/21/2025] [Accepted: 02/22/2025] [Indexed: 02/28/2025]
Abstract
B cells play a key role in the pathophysiology of systemic sclerosis (SSc). While they are less characterized than their circulating counterparts, tissue-infiltrating B cells may have a more direct pathological role in tissues. In this review, we decipher the multiple evidence of B cells infiltration in the skin and lungs of SSc patients and animal models of SSc but also of other chronic fibrotic diseases with similar pathological mechanisms such as chronic graft versus host disease, idiopathic pulmonary fibrosis or morphea. We also recapitulate the current knowledge about mechanisms of B cells infiltration and their functions in tissues. Finally, we discuss B cell targeted therapies, and their specific impact on infiltrated B cells. Understanding the local consequences of infiltrating B cells is an important step for a better management of patients and the improvement of therapies in SSc.
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Affiliation(s)
- Mathilde Le Maître
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France.
| | - Thomas Guerrier
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France
| | - Sébastien Sanges
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases (ReCONNET), France
| | - Aurélien Chepy
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases (ReCONNET), France
| | - Aurore Collet
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France; CHU Lille, Institut d'Immunologie, Pôle de Biologie Pathologie Génétique, Lille, France
| | - David Launay
- Univ. Lille, Inserm, CHU Lille, U1286 - INFINITE - Institute for Translational Research in Inflammation, Lille, France; CHU Lille, Département de Médecine Interne et Immunologie Clinique, F-59000 Lille, France; Centre National de Référence Maladies Auto-immunes Systémiques Rares du Nord, Nord-Ouest, Méditerranée et Guadeloupe (CeRAINOM), F-59000 Lille, France; Health Care Provider of the European Reference Network on Rare Connective Tissue and Musculoskeletal Diseases (ReCONNET), France
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Choi JK, Mbanefo EC, Yadav MK, Alhakeem SA, Nagarajan V, Nunes NS, Kanakry CG, Egwuagu CE. Interleukin 35-producing B cells prolong the survival of GVHD mice by secreting exosomes with membrane-bound IL-35 and upregulating PD-1/LAG-3 checkpoint proteins. Theranostics 2025; 15:3610-3626. [PMID: 40093899 PMCID: PMC11905137 DOI: 10.7150/thno.105069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 01/18/2025] [Indexed: 03/19/2025] Open
Abstract
Background: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective treatment for aggressive hematologic malignancies. However, the risk of developing graft-versus-host disease (GVHD) is a significant barrier to allo-HSCT. GVHD is a debilitating condition with high mortality rates and current therapeutic options for GVHD are limited, with corticosteroids being the standard treatment. However, the adverse effects of steroids make prolonged use difficult, necessitating the development of safer therapies. IL-35-producing B-cells (i35-Bregs) have emerged as critical regulators of immunity during autoimmune diseases. In this study, we investigated whether i35-Bregs immunotherapy can suppress and mitigate GVHD. Methods: We administered a single dose of i35-Bregs (1.5×106) to mice undergoing allo-HSCT and monitored disease severity and survival of GVHD mice over 90 days post-transplantation. We discovered that i35-Bregs secrete exosomes containing membrane-bound IL-35 (i35-Exosomes) and investigated whether ex-vivo generated i35-exosomes can be used as stand-alone immunotherapy for GVHD. i35-Breg-induced expression of cytokines or checkpoint proteins (PD-1, LAG-3, CTLA-4) was analyzed by Flow cytometry, ELISA, and RNA-seq analysis. Characterization of membrane-bound IL-35 was by Proximity ligation assay (PLA), immunohistochemistry/Confocal microscopy and Alpha Fold-Multimer modeling. Results: A single dose of 1.5×106 i35-Breg reduced severity of GVHD and prolonged GVHD survival, with more than 70% i35-Breg-treated mice surviving beyond day-90 post-transplantation while observing 100% mortality among untreated mice by day-45. Contrary to the view that IL-35 is secreted cytokine, we show here that i35-Bregs mitigate GVHD via membrane-bound IL-35 and by secreting i35-exosomes. Furthermore, i35-Bregs or ex-vivo generated i35-exosomes induce alloreactive T-cells to upregulate checkpoint proteins associated with T-cell exhaustion and anergy, inhibiting alloreactive responses and propagating infectious-tolerance mechanisms that suppress GVHD. Importantly, i35-Bregs or i35-exosomes suppresses GVHD by increasing bystander lymphocytes coated with immunosuppressive i35-exosomes. Conclusions: This study demonstrates that i35-Bregs and i35-exosomes play a critical role in mitigating GVHD. The combination of i35-Breg and i35-exosome immunotherapy may be an effective strategy for treating GVHD and other inflammatory diseases.
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Affiliation(s)
- Jin Kyeong Choi
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
- Department of Immunology, Jeonbuk National University Medical School, Jeonju, Jeonbuk, 54907, Republic of Korea
| | - Evaristus C. Mbanefo
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
| | - Manoj Kumar Yadav
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
| | - Sahar A. Alhakeem
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
- Department of Biomedical Sciences, College of Health Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI, United States
| | - Vijayaraj Nagarajan
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
| | - Natalia S. Nunes
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, United States of America
| | - Christopher G. Kanakry
- Center for Immuno-Oncology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda MD 20892, United States of America
| | - Charles E. Egwuagu
- Molecular Immunology Section, Laboratory of Immunology, National Eye Institute (NEI), National Institutes of Health (NIH), Bethesda, MD 20892, United States of America (USA)
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Gao Y, Liu R, Shi J, Shan W, Zhou H, Chen Z, Yue X, Zhang J, Luo Y, Pan W, Zhao X, Zeng X, Yin W, Xiao H. Clonal GZMK +CD8 + T cells are identified as a hallmark of the pathogenesis of cGVHD-induced bronchiolitis obliterans syndrome after allogeneic hematopoietic stem cell transplantation. EBioMedicine 2025; 112:105535. [PMID: 39740295 PMCID: PMC11750515 DOI: 10.1016/j.ebiom.2024.105535] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2024] [Revised: 12/13/2024] [Accepted: 12/17/2024] [Indexed: 01/02/2025] Open
Abstract
BACKGROUND Bronchiolitis obliterans syndrome (BOS) is one of the most devastating outcomes of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). This remains an area of unmet clinical need for optimal therapy for BOS patients partly due to the limited understanding of pathogenic mechanisms. METHODS We collected blood samples from 22 patients with cGVHD and 11 patients without cGVHD following allo-HSCT. By applying a combination of mass cytometry (CyTOF), RNA-sequencing and the quantitative cytokine array, we discovered a new cellular hallmarker of patients with cGVHD-BOS. This finding was further validated in cGVHD-BOS murine models by using single-cell RNA sequencing (scRNA-seq) and paired single-cell V(D)J sequencing analyses. FINDINGS We revealed that circulating Granzyme K (GZMK)-expressing CD8+ T cells with increased expression of CCR5 were accumulated in cGVHD-BOS patients, and GZMK can induce the expression of fibrosis-essential proteins, collagen type I alpha 1 chain (COL1A1) and fibronectin (FN1), in human fibroblasts. As compared to those of control mice, GZMK+CD8+ T cells in the lungs of cGVHD-BOS mice were undergoing significant infiltration and clonal hyperexpansion, with more cytotoxic, pro-inflammatory, migratory and exhausted phenotypes. Moreover, we screened small-molecule drugs and revealed that Bosutinib, the second-generation BCR-ABL1-targeting tyrosine kinase inhibitor (TKI), could inhibit GZMK expression in CD8+ T cells and reduce lung stiffness and pulmonary fibrosis in cGVHD-BOS mice. INTERPRETATION This study provides proof-of-principle evidence for clonal GZMK+CD8+ T cells as an unexplored contributor to the pathogenesis of cGVHD-BOS, which can be an underlying biomarker for treatment. FUNDING This work was supported by the National Natural Science Foundation of China (No. 82170141, 82100123, 81870136), and "Pioneer" and "Leading Goose" R&D Program of Zhejiang (grant No. 2022C03012).
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Affiliation(s)
- Yang Gao
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Ruixiang Liu
- Zhejiang Puluoting Health Technology Co., Ltd, Hangzhou, Zhejiang province, PR China
| | - Jiawei Shi
- Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang province, PR China
| | - Wei Shan
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Hongyu Zhou
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Zhi Chen
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Xiaoyan Yue
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Jie Zhang
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Yi Luo
- Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Wenjue Pan
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Xiujie Zhao
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China
| | - Xun Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China.
| | - Weiwei Yin
- Key Laboratory for Biomedical Engineering of the Ministry of Education, College of Biomedical Engineering and Instrument Science, Zhejiang University, Hangzhou, Zhejiang province, PR China; Zhejiang Provincial Key Laboratory of Cardio-Cerebral Vascular Detection Technology and Medicinal Effectiveness Appraisal, College of Biomedical Engineering and Instrument of Science, Zhejiang University, Hangzhou, Zhejiang province, PR China.
| | - Haowen Xiao
- Department of Hematology and Cell Therapy, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang province, PR China.
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Nishimura Y, Tsuchiya T, Kijima K, Matsuhira T. [Pharmacological and clinical profiles of belumosudil mesylate (REZUROCK ® Tablets), a selective inhibitor of ROCK2]. Nihon Yakurigaku Zasshi 2025; 160:141-151. [PMID: 40024700 DOI: 10.1254/fpj.24091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2025]
Abstract
Belumosudil mesylate (REZUROCK® Tablets hereafter belumosudil) is a novel selective rho-associated, coiled-coil containing protein kinase 2 (ROCK2) inhibitor. ROCK2 is a kinase involved in immune cell differentiation and tissue fibrosis. Belumosudil exerts its effect by decreasing the inflammation and fibrosis in various organs which are the two key features of cGVHD. In the phase III clinical study in Japan, the primary endpoint was met, best overall response rate (best ORR), defined as the percentage of patients who achieved complete response (CR) or partial response (PR), was 85.7%. Belumosudil received manufacturing and marketing approval for the treatment of chronic graft-versus-host disease (cGVHD) in patients who have insufficient response to steroid therapy in March 2024 and launched in May 2024. The Japanese MHLW has also granted orphan drug designation in May 2023 for the treatment of cGVHD.
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Jang E, Youn J. Contribution of long-lived plasma cells to antibody-mediated allograft rejection. CLINICAL TRANSPLANTATION AND RESEARCH 2024; 38:341-353. [PMID: 39690904 PMCID: PMC11732765 DOI: 10.4285/ctr.24.0047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2024] [Revised: 11/15/2024] [Accepted: 11/15/2024] [Indexed: 12/19/2024]
Abstract
Persistent alloantigens derived from allograft tissues can be recognized by the host's alloreactive immune system. This process enables cognate B cells to differentiate into plasma cells, which secrete donor-specific antibodies that are key drivers of antibody-mediated allograft rejection. A subset of these plasma cells can survive for extended periods in a suitable survival niche and mature into long-lived plasma cells (LLPCs), which are a cellular component of humoral memory. The current understanding of LLPCs is limited due to their scarcity, heterogeneity, and absence of unique markers. However, accumulating evidence indicates that LLPCs, unlike conventional short-lived plasma cells, can respond to extrinsic signals from their survival niches and can resist cell death associated with intracellular stress through cell-intrinsic mechanisms. Notably, they are refractory to traditional immunosuppressants and B cell depletion therapies. This resistance, coupled with their longevity, may explain why current treatments targeting antibody-mediated rejection are often ineffective. This review offers insights into the biology of LLPCs and discusses ongoing therapeutic trials that target LLPCs in the context of antibody-mediated allograft rejection.
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Affiliation(s)
- Eunkyeong Jang
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul, Korea
| | - Jeehee Youn
- Laboratory of Autoimmunology, Department of Anatomy and Cell Biology, Hanyang University College of Medicine, Seoul, Korea
- Department of Biomedical Science, Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Korea
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Deng K, Lu G. Immune dysregulation as a driver of bronchiolitis obliterans. Front Immunol 2024; 15:1455009. [PMID: 39742269 PMCID: PMC11685133 DOI: 10.3389/fimmu.2024.1455009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Accepted: 11/29/2024] [Indexed: 01/03/2025] Open
Abstract
Bronchiolitis obliterans (BO) is a disease characterized by airway obstruction and fibrosis that can occur in all age groups. Bronchiolitis obliterans syndrome (BOS) is a clinical manifestation of BO in patients who have undergone lung transplantation or hematopoietic stem cell transplantation. Persistent inflammation and fibrosis of small airways make the disease irreversible, eventually leading to lung failure. The pathogenesis of BO is not entirely clear, but immune disorders are commonly involved, with various immune cells playing complex roles in different BO subtypes. Accordingly, the US Food and Drug Administration (FDA) has recently approved several new drugs that can alleviate chronic graft-versus-host disease (cGVHD) by regulating the function of immune cells, some of which have efficacy specifically with cGVHD-BOS. In this review, we will discuss the roles of different immune cells in BO/BOS, and introduce the latest drugs targeting various immune cells as the main target. This study emphasizes that immune dysfunction is an important driving factor in its pathophysiology. A better understanding of the role of the immune system in BO will enable the development of targeted immunotherapies to effectively delay or even reverse this condition.
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Affiliation(s)
| | - Gen Lu
- Department of Respiration, Guangzhou Women and Children’s Medical Centre, Guangzhou Medical University, Guangzhou, Guangdong, China
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Boiko JR, Hill GR. Chronic Graft-versus-host Disease: Immune Insights, Therapeutic Advances, and Parallels for Solid Organ Transplantation. Transplantation 2024:00007890-990000000-00959. [PMID: 39682018 DOI: 10.1097/tp.0000000000005298] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2024]
Abstract
Chronic graft-versus-host disease remains a frequent and morbid outcome of allogeneic hematopoietic cell transplantation, in which the donor-derived immune system attacks healthy recipient tissue. Preceding tissue damage mediated by chemoradiotherapy and alloreactive T cells compromise central and peripheral tolerance mechanisms, leading to aberrant donor T cell and germinal center B cell differentiation, culminating in pathogenic macrophage infiltration and differentiation in a target tissue, with ensuant fibrosis. This process results in a heterogeneous clinical syndrome with significant morbidity and mortality, frequently requiring prolonged therapy. In this review, we discuss the processes that interrupt immune tolerance, the subsequent clinical manifestations, and new Food and Drug Administration-approved therapeutic approaches that have been born from a greater understanding of disease pathogenesis in preclinical systems, linking to parallel processes following solid organ transplantation.
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Affiliation(s)
- Julie R Boiko
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Pediatrics, University of Washington, Seattle, WA
| | - Geoffrey R Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
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Lee SK, Park SS, Park S, Lee SE, Cho BS, Eom KS, Kim YJ, Kim HJ, Min CK, Cho SG, Lee JW, Lee S, Kim Y, Han JW, Yang H, Bae SH, Jang JW, Choi JY, Yoon SK, Lee DY, Lee SH, Yoon JH, Sung PS. The Impact of Histologic Portal T-Cell Density on the Clinical Outcomes in Hepatic Graft-versus-Host Disease and Autoimmune Liver Diseases. Diagnostics (Basel) 2024; 14:1745. [PMID: 39202234 PMCID: PMC11353783 DOI: 10.3390/diagnostics14161745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2024] [Revised: 08/05/2024] [Accepted: 08/08/2024] [Indexed: 09/03/2024] Open
Abstract
Hepatic graft-versus-host disease (GVHD) significantly impacts morbidity and mortality among allogeneic hematopoietic stem cell transplant recipients. However, the relationship between clinical and immunopathological phenotypes and their influence on clinical outcomes in hepatic GVHD is not well understood. In this study, we aimed to study the implications of portal T-cell infiltration on the clinical outcomes in hepatic GHVD and its similarities to autoimmune liver disease. We analyzed 78 patients with biopsy-confirmed hepatic GVHD (n = 38) or autoimmune liver disease (n = 40) between 2016 and 2021. The cholestatic variant was defined by an R-value < 2.0, based on the ratio of alanine aminotransferase to alkaline phosphatase. The primary outcome was the biochemical response at 4 (early) and 8-12 (late) weeks after corticosteroid treatment. In hepatic GVHD patients, the hepatitic variant (n = 19) showed greater CD3+ T-cell infiltration than the cholestatic variant (n = 19; p < 0.001). No significant differences were observed in the infiltration of CD20+, CD38+, or CD68+ cells. The hepatitic variant had significantly better early and late responses and higher liver-related event-free survival than the cholestatic variants (p < 0.05). Concerning autoimmune liver diseases, the autoimmune hepatitis (AIH) group had significantly more portal T-cell infiltration and better treatment responses than the primary biliary cholangitis (PBC) group. In conclusion, higher portal T-cell infiltration may be associated with better clinical outcomes in patients with hepatic GVHD. Additionally, this study highlights similarities in portal T-cell infiltration and treatment response patterns between AIH and the hepatitic variant, as well as PBC and the cholestatic variant.
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Affiliation(s)
- Soon Kyu Lee
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Incheon St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
| | - Sung-Soo Park
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Silvia Park
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Sung-Eun Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Byung-Sik Cho
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Ki-Seong Eom
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Yoo-Jin Kim
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Hee-Je Kim
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Chang-Ki Min
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Seok-Goo Cho
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Jong Wook Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Seok Lee
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Younghoon Kim
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Ji Won Han
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Hyun Yang
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Si Hyun Bae
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Eunpyeong St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jeong Won Jang
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Jong Young Choi
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Seung Kew Yoon
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Dong Yeup Lee
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
| | - Sung Hak Lee
- Department of Hospital Pathology, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea;
| | - Jae-Ho Yoon
- Department of Hematology, Catholic Hematology Hospital and Leukemia Research Institute, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (S.-S.P.); (S.P.); (S.-E.L.); (B.-S.C.); (K.-S.E.); (Y.-J.K.); (H.-J.K.); (C.-K.M.); (S.-G.C.); (J.W.L.); (S.L.)
| | - Pil Soo Sung
- The Catholic University Liver Research Centre, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea; (J.W.H.); (H.Y.); (S.H.B.); (J.W.J.); (J.Y.C.); (S.K.Y.); (D.Y.L.)
- Division of Gastroenterology and Hepatology, Department of Internal Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul 06591, Republic of Korea
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9
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Singh RB, Cho W, Liu C, Naderi A, Surico PL, Kahale F, Dohlman TH, Chauhan SK, Dana R. Immunopathological mechanisms and clinical manifestations of ocular graft-versus-host disease following hematopoietic stem cell transplantation. Bone Marrow Transplant 2024; 59:1049-1056. [PMID: 38822141 DOI: 10.1038/s41409-024-02321-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2024] [Revised: 05/21/2024] [Accepted: 05/23/2024] [Indexed: 06/02/2024]
Abstract
Graft-versus-host disease is among the most common clinical complications following allogeneic hematopoietic stem cell transplantation. It causes inflammation-mediated destruction and dysfunction of various organ systems including ocular tissues in 60-90% of the patients and is termed ocular GVHD (oGVHD). In oGVHD, donor-derived T-cells recognize host antigens as foreign, resulting in immune dysregulation, inflammation and fibrosis of lacrimal glands, meibomian glands, cornea, and conjunctiva. The clinical presentation in oGVHD patients range from mild dry eye symptoms to catastrophic inflammation mediated pathological changes which can cause corneal perforation and blindness. In this review article, we provide detailed insights into the impact of mucosal barrier disruption, the afferent and efferent phases of immunological response involving activation of antigen presenting cells and T cells, respectively. We evaluate the evidence outlining the effector phase of the disease leading to cellular destruction and eventually fibrosis in patients with oGVHD. Finally, we discuss the well-established criteria for the diagnosis of oGVHD.
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Affiliation(s)
- Rohan Bir Singh
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Wonkyung Cho
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Catherine Liu
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Amirreza Naderi
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Pier Luigi Surico
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Francesca Kahale
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Thomas H Dohlman
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Sunil K Chauhan
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA
| | - Reza Dana
- Laboratory of Ocular Immunology, Transplantation and Regeneration, Schepens Eye Research Institute, Massachusetts Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA, USA.
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10
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Choi HJ, Wu Y, Mcdaniel Mims B, Pugel A, Tang CHA, Tian L, Hu CCA, Yu XZ. Endoplasmic Reticulum Stress Response Mediator IRE-1α Promotes Host Dendritic Cells in Graft-versus-Host Disease Development. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 213:384-393. [PMID: 38864663 PMCID: PMC11415232 DOI: 10.4049/jimmunol.2300616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Accepted: 05/22/2024] [Indexed: 06/13/2024]
Abstract
Allogeneic hematopoietic cell transplantation is an effective treatment for hematologic malignancies, but the complications such as graft-versus-host disease (GVHD) can limit its benefit. The conditioning regimens before transplant, including chemotherapy or irradiation, can trigger endoplasmic reticulum stress. IRE-1α is a major endoplasmic reticulum stress mediator that can further activate both spliced XBP-1 (XBP-1s) and regulated IRE-1-dependent decay (RIDD). IRE-1α-XBP-1s signaling controls dendritic cell (DC) differentiation and Ag presentation, crucial in GVHD progression. In this study, we used DC-specific XBP-1-deficient mice as donors or recipients and observed that XBP-1s was crucial for host DCs in the induction of GVHD but dispensable for the graft-versus-leukemia response. To specifically target IRE-1α in the host, we treated recipient mice with the IRE-1α inhibitor B-I09 for 3 d prior to bone marrow transplantation, which significantly suppressed GVHD development while maintaining the graft-versus-leukemia effect. XBP-1-deficient or BI09-treated recipients showed reduced DC survival after irradiation and bone marrow transplantation. Inhibition of IRE-1α also led to a reduction in DC alloreactivity, subsequently decreasing the proliferation and activation of allogeneic T cells. With further study using RIDD-deficient DCs, we observed that RIDD was also required for optimal DC activation. Taken together, XBP-1s and RIDD both promote host DC survival and alloreactivity that contribute to GVHD development.
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Affiliation(s)
- Hee-Jin Choi
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Yongxia Wu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Brianyell Mcdaniel Mims
- Department of Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Allison Pugel
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Chih-Hang Anthony Tang
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, United States
| | - Linlu Tian
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
| | - Chih-Chi Andrew Hu
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Neal Cancer Center, Houston Methodist Research Institute, Houston, TX, United States
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, USA
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11
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He J, Zheng F, Zhang L, Cai J, Ogawa Y, Tsubota K, Liu S, Jin X. Single-cell RNA-sequencing reveals the transcriptional landscape of lacrimal gland in GVHD mouse model. Ocul Surf 2024; 33:50-63. [PMID: 38703817 DOI: 10.1016/j.jtos.2024.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2023] [Revised: 04/02/2024] [Accepted: 04/26/2024] [Indexed: 05/06/2024]
Abstract
PURPOSE To investigate the global transcriptional landscape of lacrimal gland cell populations in the GVHD mouse model. METHODS Single-cell RNA sequencing and further bioinformatic analysis of dissociated lacrimal gland (LG) cells from the mouse model were performed. Parts of transcriptional results were confirmed by immunofluorescence staining. RESULTS We identified 23 cell populations belonging to 11 cell types. In GVHD LG, the proportion of acinar cells, myoepithelial cells, and endothelial cells was remarkably decreased, while T cells and macrophages were significantly expanded. Gene expression analysis indicated decreased secretion function, extracellular matrix (ECM) synthesis, and increased chemokines of myoepithelial cells. A newly described epithelial population named Lrg1high epithelial cells, expressing distinct gene signatures, was exclusively identified in GVHD LG. The fibroblasts exhibited an inflammation gene pattern. The gene pattern of endothelial cells suggested an increased ability to recruit immune cells and damaged cell-cell junctions. T cells were mainly comprised of Th2 cells and effective memory CD8+ T cells. GVHD macrophages exhibited a Th2 cell-linked pattern. CONCLUSIONS This single-cell atlas uncovered alterations of proportion and gene expression patterns of cell populations and constructed cell-cell communication networks of GVHD LG. These data may provide some new insight into understanding the development of ocular GVHD.
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Affiliation(s)
- Jingliang He
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | - Fang Zheng
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | - Li Zhang
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China
| | | | - Yoko Ogawa
- Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan
| | - Kazuo Tsubota
- Department of Ophthalmology, Keio University, School of Medicine, Tokyo, Japan; Tsubota Laboratory, Inc., Tokyo, Japan
| | - Shan Liu
- Department of Ophthalmology, Shanghai General Hospital (Shanghai First People's Hospital), Shanghai Jiao Tong University School of Medicine, Shanghai, China; Shanghai Key Laboratory of Ocular Fundus Diseases, Shanghai, China
| | - Xiuming Jin
- Eye Center, The Second Affiliated Hospital, School of Medicine, Zhejiang University, China; Zhejiang Provincial Key Laboratory of Ophthalmology, Zhejiang Provincial Clinical Research Center for Eye Diseases, China; Zhejiang Provincial Engineering Institute on Eye Diseases, Hangzhou, Zhejiang, China.
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12
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von Hofsten S, Fenton KA, Pedersen HL. Human and Murine Toll-like Receptor-Driven Disease in Systemic Lupus Erythematosus. Int J Mol Sci 2024; 25:5351. [PMID: 38791389 PMCID: PMC11120885 DOI: 10.3390/ijms25105351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2024] [Revised: 05/10/2024] [Accepted: 05/12/2024] [Indexed: 05/26/2024] Open
Abstract
The pathogenesis of systemic lupus erythematosus (SLE) is linked to the differential roles of toll-like receptors (TLRs), particularly TLR7, TLR8, and TLR9. TLR7 overexpression or gene duplication, as seen with the Y-linked autoimmune accelerator (Yaa) locus or TLR7 agonist imiquimod, correlates with increased SLE severity, and specific TLR7 polymorphisms and gain-of-function variants are associated with enhanced SLE susceptibility and severity. In addition, the X-chromosome location of TLR7 and its escape from X-chromosome inactivation provide a genetic basis for female predominance in SLE. The absence of TLR8 and TLR9 have been shown to exacerbate the detrimental effects of TLR7, leading to upregulated TLR7 activity and increased disease severity in mouse models of SLE. The regulatory functions of TLR8 and TLR9 have been proposed to involve competition for the endosomal trafficking chaperone UNC93B1. However, recent evidence implies more direct, regulatory functions of TLR9 on TLR7 activity. The association between age-associated B cells (ABCs) and autoantibody production positions these cells as potential targets for treatment in SLE, but the lack of specific markers necessitates further research for precise therapeutic intervention. Therapeutically, targeting TLRs is a promising strategy for SLE treatment, with drugs like hydroxychloroquine already in clinical use.
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Affiliation(s)
- Susannah von Hofsten
- Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway;
| | - Kristin Andreassen Fenton
- Centre of Clinical Research and Education, University Hospital of North Norway, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway;
| | - Hege Lynum Pedersen
- Centre of Clinical Research and Education, University Hospital of North Norway, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, 9019 Tromsø, Norway;
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13
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Bracken SJ, Suthers AN, DiCioccio RA, Su H, Anand S, Poe JC, Jia W, Visentin J, Basher F, Jordan CZ, McManigle WC, Li Z, Hakim FT, Pavletic SZ, Bhuiya NS, Ho VT, Horwitz ME, Chao NJ, Sarantopoulos S. Heightened TLR7 signaling primes BCR-activated B cells in chronic graft-versus-host disease for effector functions. Blood Adv 2024; 8:667-680. [PMID: 38113462 PMCID: PMC10839617 DOI: 10.1182/bloodadvances.2023010362] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Revised: 11/02/2023] [Accepted: 11/20/2023] [Indexed: 12/21/2023] Open
Abstract
ABSTRACT Chronic graft-versus-host disease (cGVHD) is a debilitating, autoimmune-like syndrome that can occur after allogeneic hematopoietic stem cell transplantation. Constitutively activated B cells contribute to ongoing alloreactivity and autoreactivity in patients with cGVHD. Excessive tissue damage that occurs after transplantation exposes B cells to nucleic acids in the extracellular environment. Recognition of endogenous nucleic acids within B cells can promote pathogenic B-cell activation. Therefore, we hypothesized that cGVHD B cells aberrantly signal through RNA and DNA sensors such as Toll-like receptor 7 (TLR7) and TLR9. We found that B cells from patients and mice with cGVHD had higher expression of TLR7 than non-cGVHD B cells. Using ex vivo assays, we found that B cells from patients with cGVHD also demonstrated increased interleukin-6 production after TLR7 stimulation with R848. Low-dose B-cell receptor (BCR) stimulation augmented B-cell responses to TLR7 activation. TLR7 hyperresponsiveness in cGVHD B cells correlated with increased expression and activation of the downstream transcription factor interferon regulatory factor 5. Because RNA-containing immune complexes can activate B cells through TLR7, we used a protein microarray to identify RNA-containing antigen targets of potential pathological relevance in cGVHD. We found that many of the unique targets of active cGVHD immunoglobulin G (IgG) were nucleic acid-binding proteins. This unbiased assay identified the autoantigen and known cGVHD target Ro-52, and we found that RNA was required for IgG binding to Ro-52. Herein, we find that BCR-activated B cells have aberrant TLR7 signaling responses that promote potential effector responses in cGVHD.
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Affiliation(s)
- Sonali J. Bracken
- Division of Rheumatology and Immunology, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Amy N. Suthers
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Rachel A. DiCioccio
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Hsuan Su
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Sarah Anand
- Division of Hematology and Medical Oncology, Department of Medicine, University of Michigan, Ann Arbor, MI
| | - Jonathan C. Poe
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Wei Jia
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Jonathan Visentin
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Department of Immunology and Immunogenetics, Bordeaux University Hospital, Bordeaux, France
- UMR CNRS 5164 ImmunoConcEpT, Bordeaux University, Bordeaux, France
| | - Fahmin Basher
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
| | - Collin Z. Jordan
- Division of Nephrology, Department of Medicine, Duke University Medical Center, Durham NC
| | - William C. McManigle
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke University Medical Center, Durham NC
| | - Zhiguo Li
- Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham NC
- Duke Cancer Institute, Duke University Medical Center, Durham NC
| | - Frances T. Hakim
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD
| | - Steven Z. Pavletic
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD
| | - Nazmim S. Bhuiya
- Experimental Transplantation and Immunology Branch, National Cancer Institute, Bethesda, MD
| | - Vincent T. Ho
- Division of Hematologic Malignancies and Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA
| | - Mitchell E. Horwitz
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Duke Cancer Institute, Duke University Medical Center, Durham NC
| | - Nelson J. Chao
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Duke Cancer Institute, Duke University Medical Center, Durham NC
- Department of Integrated Immunobiology, Duke University School of Medicine, Durham, NC
| | - Stefanie Sarantopoulos
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University Medical Center, Durham, NC
- Duke Cancer Institute, Duke University Medical Center, Durham NC
- Department of Integrated Immunobiology, Duke University School of Medicine, Durham, NC
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14
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Shaikh SN, Willis EF, Dierich M, Xu Y, Stuart SJS, Gobe GC, Bashaw AA, Rawashdeh O, Kim SJ, Vukovic J. CSF-1R inhibitor PLX3397 attenuates peripheral and brain chronic GVHD and improves functional outcomes in mice. J Neuroinflammation 2023; 20:300. [PMID: 38102698 PMCID: PMC10725001 DOI: 10.1186/s12974-023-02984-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2023] [Accepted: 12/03/2023] [Indexed: 12/17/2023] Open
Abstract
Graft-versus-host disease (GVHD) is a serious complication of otherwise curative allogeneic haematopoietic stem cell transplants. Chronic GVHD induces pathological changes in peripheral organs as well as the brain and is a frequent cause of late morbidity and death after bone-marrow transplantation. In the periphery, bone-marrow-derived macrophages are key drivers of pathology, but recent evidence suggests that these cells also infiltrate into cGVHD-affected brains. Microglia are also persistently activated in the cGVHD-affected brain. To understand the involvement of these myeloid cell populations in the development and/or progression of cGVHD pathology, we here utilized the blood-brain-barrier permeable colony stimulating factor-1 receptor (CSF-1R) inhibitor PLX3397 (pexidartinib) at varying doses to pharmacologically deplete both cell types. We demonstrate that PLX3397 treatment during the development of cGVHD (i.e., 30 days post-transplant) improves disease symptoms, reducing both the clinical scores and histopathology of multiple cGVHD target organs, including the sequestration of T cells in cGVHD-affected skin tissue. Cognitive impairments associated with cGVHD and neuroinflammation were also attenuated by PLX3397 treatment. PLX3397 treatment prior to the onset of cGVHD (i.e., immediately post-transplant) did not change in clinical scores or histopathology. Overall, our data demonstrate significant benefits of using PLX3397 for the treatment of cGVHD and associated organ pathologies in both the periphery and brain, highlighting the therapeutic potential of pexidartinib for this condition.
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Affiliation(s)
- Samreen N Shaikh
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Emily F Willis
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Max Dierich
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Yi Xu
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Samuel J S Stuart
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Glenda C Gobe
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Abate A Bashaw
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Oliver Rawashdeh
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Seung Jae Kim
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia
| | - Jana Vukovic
- School of Biomedical Sciences, Faculty of Medicine, The University of Queensland, St Lucia, Brisbane, QLD, 4072, Australia.
- Queensland Brain Institute, The University of Queensland, Brisbane, QLD, Australia.
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15
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Zhang H, Liu J, Sun Y, Huang J, Qi H, Shao R, Wu Q, Jiang Q, Fu R, Liu Q, Jin H. Nestin+ Mesenchymal Stromal Cells Fibrotic Transition Mediated by CD169+ Macrophages in Bone Marrow Chronic Graft-versus-Host Disease. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2023; 211:1154-1166. [PMID: 37610222 DOI: 10.4049/jimmunol.2200558] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Accepted: 07/25/2023] [Indexed: 08/24/2023]
Abstract
Chronic graft-versus-host disease (cGVHD) involves multiple organs, but little is known about bone marrow (BM) alterations caused by cGVHD. In mice and humans, we found that cGVHD is associated with BM fibrosis resulting in T cell infiltration, IgG deposition, and hematopoietic dysfunction. Macrophages and Nestin+ mesenchymal stromal cells (MSCs) participated in the process of BM fibrosis during BM cGVHD development. BM macrophage numbers were significantly increased in mice and humans with BM fibrosis associated with cGVHD. Amplified macrophages produced TGF-β1, which recruited Nestin+ MSCs forming clusters, and Nestin+ MSCs later differentiated into fibroblasts, a process mediated by increased TGF-β/Smad signaling. TLR4/MyD88-mediated activation of endoplasmic reticulum (ER) stress in macrophages is associated with fibrosis by increasing Nestin+ MSC migration and differentiation into fibroblasts. Depletion of macrophages by clodronate-containing liposomes and inhibition of ER stress by 4-phenylbutyric acid reversed BM fibrosis by inhibiting fibroblast differentiation. These studies provide insights into the pathogenesis of BM fibrosis during cGVHD development.
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Affiliation(s)
- Haiyan Zhang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Jiapei Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Yiming Sun
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Junwei Huang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Hanzhou Qi
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Ruoyang Shao
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qiaoyuan Wu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - QianLi Jiang
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Rong Fu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
| | - Qifa Liu
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, Southern Medical University, Guangdong, China
| | - Hua Jin
- Department of Hematology, Nanfang Hospital, Southern Medical University, Guangzhou, China
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16
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Izzo A, Pellegrino RA, Locci G, Cesaretti M. Acute graft versus host disease after liver transplantation: where do we stand? Minerva Surg 2023; 78:537-544. [PMID: 36883938 DOI: 10.23736/s2724-5691.23.09868-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/09/2023]
Abstract
Graft-versus-host disease (GVHD) is a rare complication after liver transplantation (LT), with an estimated incidence rate of 0.5% to 2% and a mortality rate as high as 75%. The classical target organs of GVHD include the intestines, liver, and skin. The damage of these organs is not easy to detect for the clinician as there is no widely accepted clinical or laboratory diagnostic tests; as a result, diagnosis and initiation of therapy are often delayed. Moreover, without prospective clinical trials to reference, evidence guiding therapy is limited. This review summarized the current knowledge, the potential applications and the clinical relevance of GVHD after LT, highlighting novel approaches in grading and management of GVHD.
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Affiliation(s)
- Alessandro Izzo
- Department of HPB and Liver Transplantation, Brotzu Hospital, Cagliari, Italy
| | | | - Giorgia Locci
- Department of Pathology, Brotzu Hospital, Cagliari, Italy
| | - Manuela Cesaretti
- Department of HPB and Liver Transplantation, Brotzu Hospital, Cagliari, Italy -
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17
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Buxbaum NP, Socié G, Hill GR, MacDonald KPA, Tkachev V, Teshima T, Lee SJ, Ritz J, Sarantopoulos S, Luznik L, Zeng D, Paczesny S, Martin PJ, Pavletic SZ, Schultz KR, Blazar BR. Chronic GvHD NIH Consensus Project Biology Task Force: evolving path to personalized treatment of chronic GvHD. Blood Adv 2023; 7:4886-4902. [PMID: 36322878 PMCID: PMC10463203 DOI: 10.1182/bloodadvances.2022007611] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 10/26/2022] [Accepted: 10/26/2022] [Indexed: 01/26/2023] Open
Abstract
Chronic graft-versus-host disease (cGvHD) remains a prominent barrier to allogeneic hematopoietic stem cell transplantion as the leading cause of nonrelapse mortality and significant morbidity. Tremendous progress has been achieved in both the understanding of pathophysiology and the development of new therapies for cGvHD. Although our field has historically approached treatment from an empiric position, research performed at the bedside and bench has elucidated some of the complex pathophysiology of cGvHD. From the clinical perspective, there is significant variability of disease manifestations between individual patients, pointing to diverse biological underpinnings. Capitalizing on progress made to date, the field is now focused on establishing personalized approaches to treatment. The intent of this article is to concisely review recent knowledge gained and formulate a path toward patient-specific cGvHD therapy.
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Affiliation(s)
- Nataliya P. Buxbaum
- Department of Pediatrics, Roswell Park Comprehensive Cancer Center, Buffalo, NY
| | - Gerard Socié
- Hematology-Transplantation, Assistance Publique-Hopitaux de Paris & University of Paris – INSERM UMR 676, Hospital Saint Louis, Paris, France
| | - Geoffrey R. Hill
- Division of Medical Oncology, The University of Washington, Seattle, WA
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Kelli P. A. MacDonald
- Department of Immunology, QIMR Berghofer Medical Research Institute, Brisbane, QLD, Australia
| | - Victor Tkachev
- Division of Hematology/Oncology, Boston Children's Hospital, Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA
- Department of Pediatrics, Harvard Medical School, Boston, MA
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Stephanie J. Lee
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Jerome Ritz
- Dana-Farber Cancer Institute, Harvard Medical School, Brigham and Women’s Hospital, Boston, MA
| | - Stefanie Sarantopoulos
- Department of Medicine, Division of Hematologic Malignancies and Cellular Therapy, Duke University Medical Center, Duke Cancer Institute, Durham, NC
| | - Leo Luznik
- Division of Hematologic Malignancies, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Defu Zeng
- Arthur D. Riggs Diabetes and Metabolism Research Institute, The Beckman Research Institute, Hematologic Maligancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Sophie Paczesny
- Department of Microbiology and Immunology and Cancer Immunology Program, Hollings Cancer Center, Medical University of South Carolina, Charleston, SC
| | - Paul J. Martin
- Division of Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Steven Z. Pavletic
- Immune Deficiency Cellular Therapy Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD
| | - Kirk R. Schultz
- Michael Cuccione Childhood Cancer Research Program, British Columbia Children’s Hospital, University of British Columbia, Vancouver, BC, Canada
| | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneappolis, MN
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18
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Choi HJ, Yu XZ. ER stress: an emerging regulator in GVHD development. Front Immunol 2023; 14:1212215. [PMID: 37744326 PMCID: PMC10511645 DOI: 10.3389/fimmu.2023.1212215] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 08/21/2023] [Indexed: 09/26/2023] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is a promising therapeutic option for hematologic malignancies. However, the clinical benefits of allo-HCT are limited by the development of complications including graft-versus-host disease (GVHD). Conditioning regimens, such as chemotherapy and irradiation, which are administered to the patients prior to allo-HCT, can disrupt the endoplasmic reticulum (ER) homeostasis, and induce ER stress in the recipient's cells. The conditioning regimen activates antigen-presenting cells (APCs), which, in turn, activate donor cells, leading to ER stress in the transplanted cells. The unfolded protein response (UPR) is an evolutionarily conserved signaling pathway that manages ER stress in response to cellular stress. UPR has been identified as a significant regulatory player that influences the function of various immune cells, including T cells, B cells, macrophages, and dendritic cells (DCs), in various disease progressions. Therefore, targeting the UPR pathway has garnered significant attention as a promising approach for the treatment of numerous diseases, such as cancer, neurodegeneration, diabetes, and inflammatory diseases. In this review, we summarize the current literature regarding the contribution of ER stress response to the development of GVHD in both hematopoietic and non-hematopoietic cells. Additionally, we explore the potential therapeutic implications of targeting UPR to enhance the effectiveness of allo-HCT for patients with hematopoietic malignancies.
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Affiliation(s)
| | - Xue-Zhong Yu
- Department of Microbiology & Immunology, Department of Medicine, and the Cancer Center, Medical College of Wisconsin, Milwaukee, WI, United States
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19
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Gail LM, Schell KJ, Łacina P, Strobl J, Bolton SJ, Steinbakk Ulriksen E, Bogunia-Kubik K, Greinix H, Crossland RE, Inngjerdingen M, Stary G. Complex interactions of cellular players in chronic Graft-versus-Host Disease. Front Immunol 2023; 14:1199422. [PMID: 37435079 PMCID: PMC10332803 DOI: 10.3389/fimmu.2023.1199422] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 06/07/2023] [Indexed: 07/13/2023] Open
Abstract
Chronic Graft-versus-Host Disease is a life-threatening inflammatory condition that affects many patients after allogeneic hematopoietic stem cell transplantation. Although we have made substantial progress in understanding disease pathogenesis and the role of specific immune cell subsets, treatment options are still limited. To date, we lack a global understanding of the interplay between the different cellular players involved, in the affected tissues and at different stages of disease development and progression. In this review we summarize our current knowledge on pathogenic and protective mechanisms elicited by the major involved immune subsets, being T cells, B cells, NK cells and antigen presenting cells, as well as the microbiome, with a special focus on intercellular communication of these cell types via extracellular vesicles as up-and-coming fields in chronic Graft-versus-Host Disease research. Lastly, we discuss the importance of understanding systemic and local aberrant cell communication during disease for defining better biomarkers and therapeutic targets, eventually enabling the design of personalized treatment schemes.
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Affiliation(s)
- Laura Marie Gail
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Kimberly Julia Schell
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Piotr Łacina
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Johanna Strobl
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Steven J. Bolton
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Katarzyna Bogunia-Kubik
- Laboratory of Clinical Immunogenetics and Pharmacogenetics, Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wrocław, Poland
| | - Hildegard Greinix
- Department of Internal Medicine, Division of Hematology, Medical University of Graz, Graz, Austria
| | - Rachel Emily Crossland
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | | | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
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20
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Handelsman S, Overbey J, Chen K, Lee J, Haj D, Li Y. PD-L1's Role in Preventing Alloreactive T Cell Responses Following Hematopoietic and Organ Transplant. Cells 2023; 12:1609. [PMID: 37371079 DOI: 10.3390/cells12121609] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/05/2023] [Accepted: 06/06/2023] [Indexed: 06/29/2023] Open
Abstract
Over the past decade, Programmed Death-Ligand 1 (PD-L1) has emerged as a prominent target for cancer immunotherapies. However, its potential as an immunosuppressive therapy has been limited. In this review, we present the immunological basis of graft rejection and graft-versus-host disease (GVHD), followed by a summary of biologically relevant molecular interactions of both PD-L1 and Programmed Cell Death Protein 1 (PD-1). Finally, we present a translational perspective on how PD-L1 can interrupt alloreactive-driven processes to increase immune tolerance. Unlike most current therapies that block PD-L1 and/or its interaction with PD-1, this review focuses on how upregulation or reversed sequestration of this ligand may reduce autoimmunity, ameliorate GVHD, and enhance graft survival following organ transplant.
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Affiliation(s)
- Shane Handelsman
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Juliana Overbey
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Kevin Chen
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Justin Lee
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Delour Haj
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
| | - Yong Li
- BioMedical Engineering, Department of Orthopaedic Surgery, Homer Stryker MD School of Medicine (WMed), Western Michigan University, Kalamazoo, MI 49007, USA
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21
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Sumii Y, Kondo T, Ikegawa S, Fukumi T, Iwamoto M, Nishimura MF, Sugiura H, Sando Y, Nakamura M, Meguri Y, Matsushita T, Tanimine N, Kimura M, Asada N, Ennishi D, Maeda Y, Matsuoka KI. Hematopoietic stem cell-derived Tregs are essential for maintaining favorable B cell lymphopoiesis following posttransplant cyclophosphamide. JCI Insight 2023; 8:162180. [PMID: 37092551 DOI: 10.1172/jci.insight.162180] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Accepted: 03/08/2023] [Indexed: 04/25/2023] Open
Abstract
Posttransplant cyclophosphamide (PTCy) is associated with a low incidence of chronic graft-versus-host disease (cGVHD) following hematopoietic stem cell (HSC) transplantation. Previous studies have shown the important roles of B cell immunity in cGVHD development. Here, we investigated the long-term reconstitution of B lymphopoiesis after PTCy using murine models. We first demonstrated that the immune homeostatic abnormality leading to cGVHD is characterized by an initial increase in effector T cells in the bone marrow and subsequent B and Treg cytopenia. PTCy, but not cyclosporine A or rapamycin, inhibits the initial alloreactive T cell response, which restores intra-bone marrow B lymphogenesis with a concomitant vigorous increase in Tregs. This leads to profound changes in posttransplant B cell homeostasis, including decreased B cell activating factors, increased transitional and regulatory B cells, and decreased germinal center B cells. To identify the cells responsible for PTCy-induced B cell tolerance, we selectively depleted Treg populations that were graft or HSC derived using DEREG mice. Deletion of either Treg population without PTCy resulted in critical B cytopenia. PTCy rescued B lymphopoiesis from graft-derived Treg deletion. In contrast, the negative effect of HSC-derived Treg deletion could not be overcome by PTCy, indicating that HSC-derived Tregs are essential for maintaining favorable B lymphopoiesis following PTCy. These findings define the mechanisms by which PTCy restores homeostasis of the B cell lineage and reestablishes immune tolerance.
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Affiliation(s)
- Yuichi Sumii
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Takumi Kondo
- Department of Hematology, Oncology and Respiratory Medicine and
| | | | - Takuya Fukumi
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Miki Iwamoto
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Midori Filiz Nishimura
- Department of Pathology, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan
| | | | - Yasuhisa Sando
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Makoto Nakamura
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Yusuke Meguri
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Takashi Matsushita
- Department of Dermatology, Faculty of Medicine, College of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Naoki Tanimine
- Department of Gastroenterological and Transplant Surgery, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Japan
| | - Maiko Kimura
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Noboru Asada
- Department of Hematology and Oncology, Okayama University Hospital, Okayama, Japan
| | - Daisuke Ennishi
- Department of Hematology, Oncology and Respiratory Medicine and
| | - Yoshinobu Maeda
- Department of Hematology, Oncology and Respiratory Medicine and
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22
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Holtan SG, Savid-Frontera C, Walton K, Eaton AA, Demorest C, Hoeschen A, Zhang L, Reid K, Kurian T, Sayegh Z, Julia E, Maakaron J, Bachanova V, Jurdi NE, MacMillan ML, Weisdorf DJ, Felices M, Miller JS, Blazar BR, Davila ML, Betts BC. Human Effectors of Acute and Chronic GVHD Overexpress CD83 and Predict Mortality. Clin Cancer Res 2023; 29:1114-1124. [PMID: 36622700 PMCID: PMC10011883 DOI: 10.1158/1078-0432.ccr-22-2837] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2022] [Revised: 10/31/2022] [Accepted: 01/05/2023] [Indexed: 01/10/2023]
Abstract
PURPOSE Acute and chronic GVHD remain major causes of transplant-related morbidity and mortality (TRM) after allogeneic hematopoietic cell transplantation (alloHCT). We have shown CD83 chimeric antigen receptor (CAR) T cells prevent GVHD and kill myeloid leukemia cell lines. In this pilot study, we investigate CD83 expression on GVHD effector cells, correlate these discoveries with clinical outcomes, and evaluate critical therapeutic implications for transplant recipients. EXPERIMENTAL DESIGN CD83 expression was evaluated among circulating CD4+ T cells, B-cell subsets, T follicular helper (Tfh) cells, and monocytes from patients with/without acute or chronic GVHD (n = 48 for each group), respectively. CD83 expression was correlated with survival, TRM, and relapse after alloHCT. Differential effects of GVHD therapies on CD83 expression was determined. RESULTS CD83 overexpression on CD4+ T cells correlates with reduced survival and increased TRM. Increased CD83+ B cells and Tfh cells, but not monocytes, are associated with poor posttransplant survival. CD83 CAR T eliminate autoreactive CD83+ B cells isolated from patients with chronic GVHD, without B-cell aplasia as observed with CD19 CAR T. We demonstrate robust CD83 antigen density on human acute myeloid leukemia (AML), and confirm potent antileukemic activity of CD83 CAR T in vivo, without observed myeloablation. CONCLUSIONS CD83 is a promising diagnostic marker of GVHD and warrants further investigation as a therapeutic target of both GVHD and AML relapse after alloHCT.
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Affiliation(s)
- Shernan G. Holtan
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Constanza Savid-Frontera
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Kelly Walton
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Anne A. Eaton
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Connor Demorest
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
| | - Andrea Hoeschen
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Ling Zhang
- Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Kayla Reid
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Tony Kurian
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Zena Sayegh
- Department of Hematopathology and Laboratory Medicine, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Estefania Julia
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Joseph Maakaron
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Veronika Bachanova
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Najla El Jurdi
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Margaret L. MacMillan
- Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Daniel J. Weisdorf
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Martin Felices
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Jeffrey S. Miller
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Bruce R. Blazar
- Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
| | - Marco L. Davila
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Brian C. Betts
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, Masonic Cancer Center, University of Minnesota, Minneapolis, Minnesota
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23
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Salhotra A, Sandhu K, O'Hearn J, Ali H, Nakamura R, Modi BG. A critical review of belumosudil in adult and pediatric patients with chronic graft-versus-host disease. Expert Rev Clin Immunol 2023; 19:241-251. [PMID: 36440483 DOI: 10.1080/1744666x.2023.2152330] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Chronic graft-versus-host disease (cGVHD) is a complication of allogeneic hematopoietic cell transplantation (allo-HCT) and is the main cause of late non-relapse mortality (NRM). Three new agents are now approved to treat cGVHD, of which belumosudil has a unique and dual mechanism of action of i) targeting the Rho-GTPase-associated coiled-coil kinase 2 (ROCK2) in T helper follicular cells (TFH) and TH17 cells, this results in downregulation of proinflammatory cytokines (interleukin -21 and 17), the former in a STAT3-dependent mechanism, ii) inhibition of tissue fibrosis by targeting stress-induced polymerization of G-actin fibrils by inhibiting the Rho-ROCK-MRTF pathway. AREAS COVERED In this review we describe the epidemiology of cGVHD, its cardinal symptoms, preventive and therapeutic options, including second-line approved therapies in the United States (US). Clinical trial data that led to approval of belumosudil is discussed, in addition to the clinical scenarios in which the approved drugs may be most applicable. EXPERT OPINION Belumosudil is approved for treatment of adult and pediatric patients ≥ 12 years with cGVHD after failing two lines of therapy based on results of the ROCKstar study that showed high overall response rates (ORR), favorable adverse effect profiles, and low rates of severe infections. With the availability of three new agents for treatment of cGVHD, treating physicians have more therapeutic options for patients and have additional options of development new clinical trials using a combination of recently approved drugs.
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Affiliation(s)
- Amandeep Salhotra
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Karamjeet Sandhu
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - James O'Hearn
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Haris Ali
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Ryotaro Nakamura
- Department of Hematology and HCT, City of Hope National Medical Center, Duarte, CA, USA
| | - Badri G Modi
- Department of Surgery, Division of Dermatology, City of Hope National Medical Center, Duarte, CA, USA
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24
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Lin C, DiCioccio RA, Haykal T, McManigle WC, Li Z, Anand SM, Poe JC, Bracken SJ, Jia W, Alyea EP, Cardones AR, Choi T, Gasparetto C, Grunwald MR, Hennig T, Kang Y, Long GD, Lopez R, Martin M, Minor KK, Quinones VLP, Sung AD, Wiggins K, Chao NJ, Horwitz ME, Rizzieri DA, Sarantopoulos S. A Phase I Trial of SYK Inhibition with Fostamatinib in the Prevention and Treatment of Chronic Graft-Versus-Host Disease. Transplant Cell Ther 2023; 29:179.e1-179.e10. [PMID: 36577483 PMCID: PMC10433369 DOI: 10.1016/j.jtct.2022.12.015] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 12/02/2022] [Accepted: 12/19/2022] [Indexed: 12/26/2022]
Abstract
Despite the exciting advancement of novel therapies, chronic graft-versus-host disease (cGVHD) remains the most common cause of non-relapse mortality after allogeneic hematopoietic stem cell transplantation (HCT). Frontline treatment of cGVHD involves systemic steroids, which are associated with significant morbidities. We previously found that inhibition of spleen tyrosine kinase (SYK) with fostamatinib preferentially eradicated aberrantly activated B cells in both ex vivo studies of cGVHD patient B cells, as well as in vivo mouse studies. These and other preclinical studies implicated hyper-reactive B-cell receptor signaling and increased SYK expression in the pathogenesis of cGVHD and compelled this first in-human allogeneic HCT clinical trial. We investigated the safety and efficacy of the oral SYK inhibitor, fostamatinib, for both the prevention and treatment of cGVHD. The primary objective was to evaluate the safety of fostamatinib and determine its maximum tolerated dose in the post-HCT setting. Secondary objectives included assessing the efficacy of fostamatinib in preventing and treating cGVHD, as well as examining alterations in B-cell compartments with treatment. This was a single-institution phase I clinical trial that evaluated the use of fostamatinib in allogeneic HCT patients before the development of cGVHD or at the time of steroid-refractory cGVHD (SR-cGVHD). Patients received fostamatinib at one of three dose levels using a continual reassessment algorithm to determine the maximum tolerated dose. Multiparameter flow cytometry was used to evaluate changes in B cell subpopulations over the first year of treatment with fostamatinib. Nineteen patients were enrolled in this phase I trial, with 5 in the prophylaxis arm and 14 in the therapeutic arm. One patient (5%) required discontinuation of therapy for a dose-limiting toxicity. At a median follow-up of over 3 years, no patients had cancer relapse while on fostamatinib treatment, and recurrent malignancy was observed in 1 patient 2 years after the end of therapy. In the prophylaxis arm, 1 of 5 patients (20%) developed cGVHD while on fostamatinib. In the therapeutic arm, the overall response rate was 77%, with a complete response rate of 31%. The median duration of response was 19.3 months and the 12-month failure-free survival was 69% (95% confidence interval, 48-100). Patients were able to reduce their steroid dose by a median of 80%, with 73% remaining on a lower dose at 1 year compared to baseline. There was an early reduction in the proportion of IgD-CD38hi plasmablast-like cells with fostamatinib treatment, particularly in those SR-cGVHD patients who had an eventual response. B-cell reconstitution was not significantly impacted by fostamatinib therapy after allogeneic HCT. Fostamatinib featured a favorable safety profile in the post-HCT setting. Our data suggests an early efficacy signal that was associated with effects on expected cell targets in both the prophylaxis and treatment of cGVHD, providing rationale for a phase II investigation.
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Affiliation(s)
- Chenyu Lin
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Rachel A DiCioccio
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Tarek Haykal
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - William C McManigle
- Division of Pulmonary and Critical Care, Department of Medicine, Medical University of South Carolina, Charleston, South Carolina
| | - Zhiguo Li
- Department of Biostatistics and Bioinformatics, Duke University School of Medicine, Durham, North Carolina
| | - Sarah M Anand
- Division of Hematology and Oncology, Department of Medicine, University of Michigan, Ann Arbor, Michigan
| | - Jonathan C Poe
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Sonali J Bracken
- Division of Rheumatology and Immunology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Wei Jia
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Edwin P Alyea
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Adela R Cardones
- Division of Dermatology, Department of Internal Medicine, University of Kansas Medical Center, Lawrence, Kansas
| | - Taewoong Choi
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Cristina Gasparetto
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Michael R Grunwald
- Department of Hematologic Oncology and Blood Disorders, Levine Cancer Institute, Atrium Health, Charlotte, North Carolina
| | - Therese Hennig
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Yubin Kang
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Gwynn D Long
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Richard Lopez
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Melissa Martin
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Kerry K Minor
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | | | - Anthony D Sung
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Kristi Wiggins
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Nelson J Chao
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | - Mitchell E Horwitz
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
| | | | - Stefanie Sarantopoulos
- Division of Hematologic Malignancies and Cellular Therapy, Department of Medicine, Duke University School of Medicine, Durham, North Carolina.
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25
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Fraebel J, Engelhardt BG, Kim TK. Noninfectious Pulmonary Complications after Hematopoietic Stem Cell Transplantation. Transplant Cell Ther 2023; 29:82-93. [PMID: 36427785 DOI: 10.1016/j.jtct.2022.11.012] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Revised: 10/31/2022] [Accepted: 11/14/2022] [Indexed: 11/24/2022]
Abstract
Pulmonary complications after hematopoietic stem cell transplantation (HSCT) are important sources of morbidity and mortality. Improvements in infection-related complications have made noninfectious pulmonary complications an increasingly significant driver of transplantation-related mortality. Broadly, these complications can be characterized as either early or late complications, with idiopathic pneumonia syndrome and bronchiolitis obliterans syndrome the most prevalent early and late complications, respectively. Outcomes with historical treatment consisting mainly of corticosteroids are often poor, highlighting the need for a deeper understanding of these complications' underlying disease biology to guide the adoption of novel therapies that are being increasingly used in the modern era.
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Affiliation(s)
- Johnathan Fraebel
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Brian G Engelhardt
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee
| | - Tae Kon Kim
- Division of Hematology/Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt Center for Immunobiology, Nashville, Tennessee; Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee; Veterans Affairs Medical Center, Tennessee Valley Healthcare System, Nashville, Tennessee.
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26
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Verlaat L, Riesner K, Kalupa M, Jung B, Mertlitz S, Schwarz C, Mengwasser J, Fricke C, Penack O. Novel pre-clinical mouse models for chronic Graft-versus-Host Disease. Front Immunol 2023; 13:1079921. [PMID: 36761159 PMCID: PMC9902926 DOI: 10.3389/fimmu.2022.1079921] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2022] [Accepted: 11/18/2022] [Indexed: 01/26/2023] Open
Abstract
Despite considerable progress in allogeneic hematopoietic cell transplantation (allo-HCT) has been achieved over the past years, chronic Graft-versus-Host Disease (cGvHD) still contributes to high morbidity rates, thus remaining a major hurdle in allo-HCT patients. To understand the complex pathophysiology of cGvHD and to develop refined prophylaxis and treatment strategies, improved pre-clinical models are needed. In this study, we developed two murine cGvHD models, which display high long-term morbidity but low mortality and depict the heterogeneous clinical manifestations of cGvHD seen in patients. We established a haploidentical C57BL/6→B6D2F1 allo-HCT model that uses myeloablative radiation and G-CSF-mobilized splenocytes as stem cell source and a sub-lethally irradiated Xenograft model, which utilizes the transfer of human peripheral blood mononuclear cells (PBMCs) into NOD scid gamma (NSG)-recipients. We characterized both mouse models to exhibit diverse clinical and histopathological signs of human cGvHD as extensive tissue damage, fibrosis/sclerosis, inflammation and B cell infiltration in cGvHD target organs skin, liver, lung and colon and found a decelerated immune cell reconstitution in the late phase after HCT. Our pre-clinical models can help to gain a deeper understanding of the target structures and mechanisms of cGvHD pathology and may enable a more reliable translation of experimental findings into the human setting of allo-HCT.
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27
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Interstitial lung diseases after hematopoietic stem cell transplantation: New pattern of lung chronic graft-versus-host disease? Bone Marrow Transplant 2023; 58:87-93. [PMID: 36309588 PMCID: PMC9812763 DOI: 10.1038/s41409-022-01859-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2021] [Revised: 10/03/2022] [Accepted: 10/14/2022] [Indexed: 01/10/2023]
Abstract
Bronchiolitis obliterans syndrome (BOS) after allogeneic HSCT is the only formally recognized manifestation of lung chronic graft-versus-host disease (GVHD). Other lung complications were reported, including interstitial lung diseases (ILDs). Whether ILDs belong to the spectrum of lung cGVHD remains unknown. We compared characteristics and specific risk factors for both ILD and BOS. Data collected from consecutive patients diagnosed with ILD or BOS from 1981-2019 were analyzed. The strength of the association between patient characteristics and ILD occurrence was measured via odds ratios estimated from univariable logistic models. Multivariable models allowed us to handle potential confounding variables. Overall survival (OS) was estimated using the Kaplan-Meier method. 238 patients were included: 79 with ILD and 159 with BOS. At diagnosis, FEV1 was lower in patients with BOS compared to patients with ILD, while DLCO was lower in ILD. 84% of ILD patients received systemic corticosteroids, leading to improved CT scans and pulmonary function, whereas most BOS patients were treated by inhaled corticosteroids, with lung-function stabilization. In the multivariable analysis, prior thoracic irradiation and absence of prior treatment with prednisone were associated with ILD. OS was similar, even if hematological relapse was more frequent in the ILD group. Both complications occurred mainly in patients with GVHD history.
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28
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Kong X, Wu X, Wang B, Zeng D, Cassady K, Nasri U, Zheng M, Wu A, Qin H, Tsai W, Salhotra A, Nakamura R, Martin PJ, Zeng D. Trafficking between clonally related peripheral T-helper cells and tissue-resident T-helper cells in chronic GVHD. Blood 2022; 140:2740-2753. [PMID: 36084473 PMCID: PMC9935547 DOI: 10.1182/blood.2022016581] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 12/30/2022] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is an autoimmune-like syndrome. CXCR5-PD-1hi peripheral T-helper (Tph) cells have an important pathogenic role in autoimmune diseases, but the role of Tph cells in cGVHD remains unknown. We show that in patients with cGVHD, expansion of Tph cells among blood CD4+ T cells was associated with cGVHD severity. These cells augmented memory B-cell differentiation and production of immunoglobulin G via interleukin 21 (IL-21). Tph cell expansion was also observed in a murine model of cGVHD. This Tph cell expansion in the blood is associated with the expansion of pathogenic tissue-resident T-helper (Trh) cells that form lymphoid aggregates surrounded by collagen in graft-versus-host disease (GVHD) target tissues. Adoptive transfer experiments showed that Trh cells from GVHD target tissues give rise to Tph cells in the blood, and conversely, Tph cells from the blood give rise to Trh cells in GVHD target tissues. Tph cells in the blood and Trh cells in GVHD target tissues had highly overlapping T-cell receptor α and β repertoires. Deficiency of IL-21R, B-cell lymphoma 6 (BCL6), or T-bet in donor T cells markedly reduced the proportions of Tph cells in the blood and Trh cells in GVHD target tissues and reduced T-B interaction in the lymphoid aggregates. These results indicate that clonally related pathogenic Tph cells and Trh cells traffic between the blood and cGVHD target tissues, and that IL-21R-BCL6 signaling and T-bet are required for the development and expansion of Tph and Trh cells in the pathogenesis of cGVHD.
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Affiliation(s)
- Xiaohui Kong
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Xiwei Wu
- Department of Integrative Genomics Core, The Beckman Research Institute of City of Hope, Duarte, CA
| | - Bixin Wang
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
- Fujian Medical University Center of Translational Hematology, Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Deye Zeng
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
- Department of Pathology, Fujian Medical University Union Hospital, Fuzhou, China
| | - Kaniel Cassady
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Ubaydah Nasri
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Moqian Zheng
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Alyssa Wu
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Hanjun Qin
- Department of Integrative Genomics Core, The Beckman Research Institute of City of Hope, Duarte, CA
| | - Weimin Tsai
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Amandeep Salhotra
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | - Ryotaro Nakamura
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
| | | | - Defu Zeng
- Department of Immunology and Theranostics, Arthur Riggs Institute of Diabetes and Metabolism Research, The Beckman Research Institute of City of Hope, Duarte, CA
- Hematologic Malignancies and Stem Cell Transplantation Institute, City of Hope National Medical Center, Duarte, CA
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29
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Watkins B, Williams KM. Controversies and expectations for the prevention of GVHD: A biological and clinical perspective. Front Immunol 2022; 13:1057694. [PMID: 36505500 PMCID: PMC9726707 DOI: 10.3389/fimmu.2022.1057694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/03/2022] [Indexed: 11/24/2022] Open
Abstract
Severe acute and chronic graft versus host disease (GVHD) remains a major cause of morbidity and mortality after allogeneic hematopoietic cell transplantation. Historically, cord blood and matched sibling transplantation has been associated with the lowest rates of GVHD. Newer methods have modified the lymphocyte components to minimize alloimmunity, including: anti-thymocyte globulin, post-transplant cyclophosphamide, alpha/beta T cell depletion, and abatacept. These agents have shown promise in reducing severe GVHD, however, can be associated with increased risks of relapse, graft failure, infections, and delayed immune reconstitution. Nonetheless, these GVHD prophylaxis strategies have permitted expansion of donor sources, especially critical for those of non-Caucasian decent who previously lacked transplant options. This review will focus on the biologic mechanisms driving GVHD, the method by which each agent impacts these activated pathways, and the clinical consequences of these modern prophylaxis approaches. In addition, emerging novel targeted strategies will be described. These GVHD prophylaxis approaches have revolutionized our ability to increase access to transplant and have provided important insights into the biology of GVHD and immune reconstitution.
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Affiliation(s)
- Benjamin Watkins
- Aflac Cancer and Blood Disorders Center, Children’s Healthcare of Atlanta, Emory University, Atlanta, GA, United States
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30
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Doglio M, Crossland RE, Alho AC, Penack O, Dickinson AM, Stary G, Lacerda JF, Eissner G, Inngjerdingen M. Cell-based therapy in prophylaxis and treatment of chronic graft-versus-host disease. Front Immunol 2022; 13:1045168. [PMID: 36466922 PMCID: PMC9714556 DOI: 10.3389/fimmu.2022.1045168] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2022] [Accepted: 10/31/2022] [Indexed: 08/31/2023] Open
Abstract
Hematopoietic allogeneic stem cell transplantation (allo-SCT) is a curative option for patients with hematological malignancies. However, due to disparities in major and minor histocompatibility antigens between donor and recipient, severe inflammatory complications can occur, among which chronic graft-versus-host disease (cGVHD) can be life-threatening. A classical therapeutic approach to the prevention and treatment of cGVHD has been broad immunosuppression, but more recently adjuvant immunotherapies have been tested. This review summarizes and discusses immunomodulatory approaches with T cells, including chimeric antigen receptor (CAR) and regulatory T cells, with natural killer (NK) cells and innate lymphoid cells (ILCs), and finally with mesenchymal stromal cells (MSC) and extracellular vesicles thereof. Clinical studies and pre-clinical research results are presented likewise.
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Affiliation(s)
- Matteo Doglio
- Experimental Haematology Unit, Division of Immunology Transplantation and Infectious Diseases, Vita-Salute San Raffaele University, Milan, Italy
| | - Rachel E. Crossland
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ana C. Alho
- JLacerda Lab, Hematology and Transplantation Immunology, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
| | - Olaf Penack
- Department of Hematology, Oncology, and Cancer Immunology, Charité Universitätsmedizin Berlin, Berlin, Germany
| | - Anne M. Dickinson
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
- Alcyomics Ltd, Newcastle upon Tyne, United Kingdom
| | - Georg Stary
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
- Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - João F. Lacerda
- JLacerda Lab, Hematology and Transplantation Immunology, Instituto de Medicina Molecular João Lobo Antunes, Faculdade de Medicina da Universidade de Lisboa, Lisbon, Portugal
- Serviço de Hematologia e Transplantação de Medula, Hospital de Santa Maria, Centro Hospitalar Universitário de Lisboa Norte, Lisbon, Portugal
| | - Günther Eissner
- Systems Biology Ireland, School of Medicine, Conway Institute, University College Dublin, Dublin, Ireland
| | - Marit Inngjerdingen
- Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
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31
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Zhang X, Zhao X, Shen Y, Shi Y, Zhang L, Hao M, Zhao F, Zhang R, Wei J, Feng S, He Y, Jiang E, Han M. Ruxolitinib as an Effective and Steroid-Sparing First-Line Treatment in Newly Diagnosed BOS Patients After Hematopoietic Stem Cell Transplantation. Front Pharmacol 2022; 13:916472. [PMID: 35865938 PMCID: PMC9294627 DOI: 10.3389/fphar.2022.916472] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2022] [Accepted: 05/03/2022] [Indexed: 11/18/2022] Open
Abstract
Bronchiolitis obliterans syndrome (BOS) is a life-threatening pulmonary complication of chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic stem cell transplantation (HSCT). In this study, we retrospectively identified seven patients newly diagnosed with BOS post HSCT and analyzed the outcomes in those patients treated with ruxolitinib as a first-line treatment. All seven patients achieved symptom responses within 2 weeks after ruxolitinib administration. Three months after treatment, five patients (71.43%) achieved a CR, and two (28.57%) achieved a PR. The overall response rate (ORR) was 100%. In addition, the steroid therapy was determined within 2 months after ruxolitinib treatment, indicating ruxolitinib as a steroid-sparing agent. We also found that ruxolitinib was well-tolerated and safe in treating newly diagnosed BOS. According to our results, ruxolitinib would be a promising and safe option in newly diagnosed BOS post HSCT.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | - Yi He
- *Correspondence: Yi He, ; Erlie Jiang,
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32
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Su H, Imai K, Jia W, Li Z, DiCioccio RA, Serody JS, Poe JC, Chen BJ, Doan PL, Sarantopoulos S. Alphavirus Replicon Particle Vaccine Breaks B Cell Tolerance and Rapidly Induces IgG to Murine Hematolymphoid Tumor Associated Antigens. Front Immunol 2022; 13:865486. [PMID: 35686131 PMCID: PMC9171395 DOI: 10.3389/fimmu.2022.865486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2022] [Accepted: 04/25/2022] [Indexed: 11/13/2022] Open
Abstract
De novo immune responses to myeloid and other blood-borne tumors are notably limited and ineffective, making our ability to promote immune responses with vaccines a major challenge. While focus has been largely on cytotoxic cell-mediated tumor eradication, B-cells and the antibodies they produce also have roles in anti-tumor responses. Indeed, therapeutic antibody-mediated tumor cell killing is routinely employed in patients with hematolymphoid cancers, but whether endogenous antibody responses can be incited to blood-born tumors remains poorly studied. A major limitation of immunoglobulin therapies is that cell surface expression of tumor-associated antigen (TAA) targets is dynamic and varied, making promotion of polyclonal, endogenous B cell responses appealing. Since many TAAs are self-antigens, developing tumor vaccines that enable production of antibodies to non-polymorphic antigen targets remains a challenge. As B cell responses to RNA vaccines are known to occur, we employed the Viral Replicon Particles (VRP) which was constructed to encode mouse FLT3. The VRP-FLT3 vaccine provoked a rapid IgG B-cell response to this self-antigen in leukemia and lymphoma mouse models. In addition, IgGs to other TAAs were also produced. Our data suggest that vaccination with RNA viral particle vectors incites a loss of B-cell tolerance that enables production of anti-tumor antibodies. This proof of principle work provides impetus to employ such strategies that lead to a break in B-cell tolerance and enable production of broadly reactive anti-TAA antibodies as potential future therapeutic agents for patients with hematolymphoid cancers.
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Affiliation(s)
- Hsuan Su
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Kazuhiro Imai
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Department of Thoracic Surgery, Akita University Graduate School of Medicine, Akita, Japan
| | - Wei Jia
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Zhiguo Li
- Biostatistics and Bioinformatics, Basic Science Department, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States
| | - Rachel A DiCioccio
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Jonathan S Serody
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States.,Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
| | - Jonathan C Poe
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States
| | - Benny J Chen
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States
| | - Phuong L Doan
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States
| | - Stefanie Sarantopoulos
- Department of Medicine, Division of Hematological Malignancies and Cellular Therapy, Duke University Medical Center, Durham, NC, United States.,Duke Cancer Institute, Duke University, Durham, NC, United States.,Department of Immunology, School of Medicine, Duke University , Durham, NC, United States
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33
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Wittenbecher F, Lesch S, Kolling S, Blau IW, Vuong L, Borchert F, Movasshagi K, Tietze-Bürger C, Penack O, Ahn J, Bullinger L, Frentsch M, Na IK. Paired Donor and Recipient Immunophenotyping in Allogeneic Hematopoietic Stem Cell Transplantation: A Cellular Network Approach. Front Immunol 2022; 13:874499. [PMID: 35677053 PMCID: PMC9168993 DOI: 10.3389/fimmu.2022.874499] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2022] [Accepted: 04/15/2022] [Indexed: 12/03/2022] Open
Abstract
Success and complications of allogeneic hematopoietic stem cell transplantation (alloHSCT) are closely connected to the transferred graft and immune reconstitution post alloHSCT. Due to the variety of immune cells and their distinct roles, a broad evaluation of the immune cellular network is warranted in mobilization and reconstitution studies in alloHSCT. Here, we propose a comprehensive phenotypic analysis of 26 immune cell subsets with multicolor flow cytometry from only 100µl whole blood per time point. Using this approach, we provide an extensive longitudinal analysis of almost 200 time points from 21 donor-recipient pairs. We observe a broad mobilization of innate and adaptive immune cell subsets after granulocyte-colony stimulating factor (G-CSF) treatment of healthy donors. Our data suggest that the relative quantitative immune cell subset composition in recipients approaches that of healthy donors from day +180 post alloHSCT onwards. Correlation of donor and recipient cell counts reveals distinct association patterns for different immune cell subsets and hierarchical clustering of recipient cell counts identifies distinct reconstitution groups in the first month after transplantation. We suggest our comprehensive immune subset analysis as a feasible and time efficient approach for a broad immune assessment for future clinical studies in the context of alloHSCT. This comprehensive cell composition assessment can be a critical step towards personalized graft composition strategies and individualized therapy management in areas such as GvHD prophylaxis in the highly complex immunological setting of alloHSCT.
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Affiliation(s)
- Friedrich Wittenbecher
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Stella Lesch
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Stefan Kolling
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Igor-Wolfgang Blau
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lam Vuong
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Franziska Borchert
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Kamran Movasshagi
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Carola Tietze-Bürger
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Olaf Penack
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Johann Ahn
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Lars Bullinger
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, ECRC Experimental and Clinical Research Center, Berlin, Germany
| | - Marco Frentsch
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany
| | - Il-Kang Na
- Department of Hematology, Oncology, and Tumor Immunology, Charite´ - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin Institute of Health, Charité - Universitätsmedizin Berlin, BIH Center for Regenerative Therapies (BCRT), Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, German Cancer Consortium (DKTK), Partner Site Berlin, Berlin, Germany.,Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt Universität zu Berlin, ECRC Experimental and Clinical Research Center, Berlin, Germany
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34
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Nasr SH, Leung N, Said SM, Alkhateeb HB, Madden BJ, Charlesworth MC, Beck LH, Larsen CP, Sethi S. Membranous Nephropathy With Extensive Tubular Basement Membrane Deposits Following Allogeneic Hematopoietic Cell Transplant: A Report of 5 Cases. Am J Kidney Dis 2022; 79:904-908. [PMID: 34508832 DOI: 10.1053/j.ajkd.2021.07.021] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 07/20/2021] [Indexed: 12/24/2022]
Abstract
Tubular basement membrane (TBM) deposits are very uncommon in non-lupus membranous nephropathy. We report 5 patients with membranous nephropathy and extensive TBM deposits following allogeneic hematopoietic cell transplant. Patients presented with nephrotic syndrome (3 also had acute kidney injury) late post-transplant in association with chronic graft-versus-host disease (cGVHD). Kidney biopsies revealed global subepithelial and extensive TBM immune complex deposits, accompanied by acute tubular injury (n = 4) and tubulointerstitial inflammation (n = 4). Proteomic analysis of glomeruli in 4 cases identified PLA2R in 1, with no significant protein spectra for PLA2R, THSD7A, EX1/2, NELL-1, PCDH7, NCAM1, or SEMA3B detected in the remaining 3. On follow-up (for a mean 42 months), 4 patients had complete and 1 partial remission following prednisone and/or rituximab therapy. We propose that membranous nephropathy with extensive TBM deposits is a distinctive clinicopathologic lesion associated with allogeneic hematopoietic cell transplant. Pathogenesis likely involves cGVHD-driven antibodies against glomerular and TBM components, the identity of which remains to be elucidated.
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Affiliation(s)
- Samih H Nasr
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | - Nelson Leung
- Division of Nephrology and Hypertension, Mayo Clinic, Rochester, Minnesota; Division of Hematology, Mayo Clinic, Rochester, Minnesota.
| | - Samar M Said
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
| | | | - Benjamin J Madden
- Medical Genome Facility, Proteomics Core, Mayo Clinic, Rochester, Minnesota
| | | | | | | | - Sanjeev Sethi
- Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota
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Zaiken MC, Flynn R, Paz KG, Rhee SY, Jin S, Mohamed FA, Saha A, Thangavelu G, Park PMC, Hemming ML, Sage PT, Sharpe AH, DuPage M, Bluestone JA, Panoskaltsis-Mortari A, Cutler CS, Koreth J, Antin JH, Soiffer RJ, Ritz J, Luznik L, Maillard I, Hill GR, MacDonald KPA, Munn DH, Serody JS, Murphy WJ, Kean LS, Zhang Y, Bradner JE, Qi J, Blazar BR. BET-bromodomain and EZH2 inhibitor-treated chronic GVHD mice have blunted germinal centers with distinct transcriptomes. Blood 2022; 139:2983-2997. [PMID: 35226736 PMCID: PMC9101246 DOI: 10.1182/blood.2021014557] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2021] [Accepted: 02/09/2022] [Indexed: 01/26/2023] Open
Abstract
Despite advances in the field, chronic graft-versus-host-disease (cGVHD) remains a leading cause of morbidity and mortality following allogenic hematopoietic stem cell transplant. Because treatment options remain limited, we tested efficacy of anticancer, chromatin-modifying enzyme inhibitors in a clinically relevant murine model of cGVHD with bronchiolitis obliterans (BO). We observed that the novel enhancer of zeste homolog 2 (EZH2) inhibitor JQ5 and the BET-bromodomain inhibitor JQ1 each improved pulmonary function; impaired the germinal center (GC) reaction, a prerequisite in cGVHD/BO pathogenesis; and JQ5 reduced EZH2-mediated H3K27me3 in donor T cells. Using conditional EZH2 knockout donor cells, we demonstrated that EZH2 is obligatory for the initiation of cGVHD/BO. In a sclerodermatous cGVHD model, JQ5 reduced the severity of cutaneous lesions. To determine how the 2 drugs could lead to the same physiological improvements while targeting unique epigenetic processes, we analyzed the transcriptomes of splenic GCB cells (GCBs) from transplanted mice treated with either drug. Multiple inflammatory and signaling pathways enriched in cGVHD/BO GCBs were reduced by each drug. GCBs from JQ5- but not JQ1-treated mice were enriched for proproliferative pathways also seen in GCBs from bone marrow-only transplanted mice, likely reflecting their underlying biology in the unperturbed state. In conjunction with in vivo data, these insights led us to conclude that epigenetic targeting of the GC is a viable clinical approach for the treatment of cGVHD, and that the EZH2 inhibitor JQ5 and the BET-bromodomain inhibitor JQ1 demonstrated clinical potential for EZH2i and BETi in patients with cGVHD/BO.
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Affiliation(s)
- Michael C Zaiken
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Ryan Flynn
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Katelyn G Paz
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Stephanie Y Rhee
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Sujeong Jin
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Fathima A Mohamed
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Asim Saha
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Govindarajan Thangavelu
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | - Paul M C Park
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
| | - Matthew L Hemming
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
| | - Peter T Sage
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA
- Evergrande Center for Immunologic Diseases, Harvard Medical School-Brigham and Women's Hospital, Boston, MA
| | - Arlene H Sharpe
- Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA
- Evergrande Center for Immunologic Diseases, Harvard Medical School-Brigham and Women's Hospital, Boston, MA
| | - Michel DuPage
- Division of Immunology and Pathogenesis, Department of Molecular and Cell Biology, University of California Berkeley, Berkeley, CA
| | | | - Angela Panoskaltsis-Mortari
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
| | | | | | | | - Robert J Soiffer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA
| | | | - Leo Luznik
- Department of Oncology, Sidney Kimmel Cancer Center, Baltimore, MD
| | - Ivan Maillard
- Division of Hematology-Oncology, Department of Medicine, University of Pennsylvania, Philadelphia, PA
| | - Geoffrey R Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
- Division of Medical Oncology, University of Washington, Seattle, WA
| | - Kelli P A MacDonald
- Department of Immunology, Queensland Institute of Medical Research (QIMR), University of Queensland, Brisbane, QLD, Australia
| | - David H Munn
- Georgia Cancer Center, Augusta University, Augusta, GA
| | - Jonathan S Serody
- Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC
| | - William J Murphy
- Department of Dermatology, School of Medicine, University of California, Davis, Sacramento, CA
| | - Leslie S Kean
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
- Boston Children's Hospital, Dana-Farber Cancer Institute, Boston, MA
| | - Yi Zhang
- Fels Institute for Cancer Research and Molecular Biology, Department of Microbiology and Immunology, Temple University, Philadelphia, PA
| | - James E Bradner
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; and
| | - Jun Qi
- Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA
- Department of Medicine, Harvard Medical School, Boston, MA
| | - Bruce R Blazar
- Division of Blood & Marrow Transplant & Cellular Therapy, Department of Pediatrics, Masonic Cancer Center, University of Minnesota, Minneapolis, MN
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Ceramide synthase 6 impacts T-cell allogeneic response and graft-versus-host disease through regulating N-RAS/ERK pathway. Leukemia 2022; 36:1907-1915. [PMID: 35513703 PMCID: PMC9256768 DOI: 10.1038/s41375-022-01581-6] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Revised: 04/09/2022] [Accepted: 04/20/2022] [Indexed: 02/02/2023]
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for various hematologic malignances, predominantly through potent graft-versus-leukemia (GVL) effect. However, the mortality after allo-HCT is because of relapse of primary malignancy and followed by graft-vs-host-disease (GVHD) as a major cause of transplant-related mortality. Hence, strategies to limit GVHD while preserving the GVL effect are highly desirable. Ceramide, which serves a central role in sphingolipid metabolism, is generated by ceramide synthases (CerS1–6). In this study, we found that genetic or pharmacologic targeting of CerS6 prevented and reversed chronic GVHD (cGVHD). Furthermore, specific inhibition of CerS6 with ST1072 significantly ameliorated acute GVHD (aGVHD) while preserving the GVL effect, which differed from FTY720 that attenuated aGVHD but impaired GVL activity. At the cellular level, blockade of CerS6 restrained donor T cells from migrating into GVHD target organs and preferentially reduced activation of donor CD4 T cells. At the molecular level, CerS6 was required for optimal TCR signaling, CD3/PKCθ co-localization, and subsequent N-RAS activation and ERK signaling, especially on CD4+ T cells. The current study provides rationale and means for targeting CerS6 to control GVHD and leukemia relapse, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.
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Dual inhibition of the MEK/ERK and PI3K/AKT pathways prevents pulmonary GVHD suppressing perivenulitis and bronchiolitis. Blood Adv 2022; 7:106-121. [PMID: 35468620 PMCID: PMC9830178 DOI: 10.1182/bloodadvances.2021006678] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 04/18/2022] [Accepted: 04/18/2022] [Indexed: 01/18/2023] Open
Abstract
Patients with pulmonary graft-versus-host disease (pGVHD) have a poor prognosis after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Furthermore, pGVHD pathogenesis is not fully elucidated in humans, and currently available immunosuppressants are inadequately effective. We performed pathologic evaluation of lung specimens from 45 allo-HSCT recipients with pGVHD who underwent lung transplantation. Patient pathology was characterized by bronchiolitis and subpleural perivascular inflammation, with B-cell, monocyte, and T-cell accumulation around bronchioles. Bronchiolitis, perivascular inflammation, and peribronchial macrophage aggregation were also identified in a murine pGVHD model after transplant of bone marrow cells and splenocytes from C57BL/6 to B10.BR mice. Among mitogen-activated protein kinase kinase (MEK) inhibitors, cobimetinib, but not trametinib, improved survival rates. Cobimetinib attenuated bronchiolitis, improved airway resistance and lung compliance in the mice, and suppressed activation of B cells and tumor necrosis factor α production by monocytes in vitro; these features were not suppressed by trametinib or tacrolimus. Furthermore, cobimetinib suppressed activation of phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling, resulting in B-cell and monocyte suppression. Dual inhibition of the MEK/extracellular signal-regulated kinase (ERK) and PI3K/AKT pathways using a combination of trametinib and the PI3K inhibitor taselisib strongly suppressed B-cell activation in vitro and improved mouse survival rates compared with vehicle or monotherapy with trametinib or taselisib. Imaging mass cytometry of human pGVHD revealed that T cells around bronchioles were positive for phosphorylated ERK, whereas B cells were positive for phosphorylated AKT. Thus, perivascular inflammation and bronchiolitis mediated by activation of the MEK/ERK and PI3K/AKT pathways are essential for pGVHD and represent a potential novel therapeutic target in humans.
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Thangavelu G, Zaiken MC, Mohamed FA, Flynn R, Du J, Rhee SY, Riddle MJ, Aguilar EG, Panoskaltsis-Mortari A, Sanders ME, Blazar BR. Targeting the Retinoid X Receptor Pathway Prevents and Ameliorates Murine Chronic Graft-Versus-Host Disease. Front Immunol 2022; 13:765319. [PMID: 35359939 PMCID: PMC8963714 DOI: 10.3389/fimmu.2022.765319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Accepted: 01/26/2022] [Indexed: 02/03/2023] Open
Abstract
Most allogeneic hematopoietic stem cell transplant (allo-HSCT) recipients receive peripheral blood stem cell grafts resulting in a 30%-70% incidence of chronic graft-versus-host disease (cGVHD), a major cause of mortality and morbidity in long-term survivors. While systemic steroids remain the standard of care for first-line therapy, patients may require long-term administration, and those with steroid-resistant or refractory cGVHD have a worse prognosis. Although durable and deep responses with second-line therapies can be achieved in some patients, there remains an urgent need for new therapies. In this study, we evaluated the efficacy of IRX4204, a novel agonist that activates RXRs and is in clinical trials for cancer treatment to prevent and treat cGVHD in two complementary murine models. In a major histocompatibility complex mismatched, non-sclerodermatous multiorgan system model with bronchiolitis obliterans, IRX4204 prevented and reversed cGVHD including associated pulmonary dysfunction with restoration of germinal center T-follicular helper: T-follicular regulatory cell balance. In a minor histocompatibility antigen disparate sclerodermatous model, IRX4204 treatment significantly prevented and ameliorated skin cGVHD by reducing Th1 and Th17 differentiation due to anti-inflammatory properties. Together, these results indicate that IRX4204 is a promising therapeutic option to treat cGVHD with bronchiolitis obliterans or sclerodermatous manifestations.
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Affiliation(s)
- Govindarajan Thangavelu
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Michael C. Zaiken
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Fathima A. Mohamed
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Ryan Flynn
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Jing Du
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Stephanie Y. Rhee
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Megan J. Riddle
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Ethan G. Aguilar
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | - Angela Panoskaltsis-Mortari
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
| | | | - Bruce R. Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, MN, United States
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Mature naive B cells regulate the outcome of murine acute graft-versus-host disease in an IL-10 independent manner. Transplant Cell Ther 2022; 28:181.e1-181.e9. [PMID: 35032717 DOI: 10.1016/j.jtct.2022.01.004] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 01/04/2022] [Accepted: 01/06/2022] [Indexed: 12/30/2022]
Abstract
Graft-versus-host disease (GVHD) is the main complication of bone marrow transplantation (BMT). T CD4+ lymphocytes are the main effector cells for disease development but other cell types can determine disease outcome through cytokine production and antigen presentation. B cells are abundant in BMT products and are involved in chronic GVHD immunopathogenesis. However, their role in acute GVHD is still unclear. Here, we studied the role of donor resting B cells in a model of acute GVHD. Animals receiving transplants depleted of B cells presented a more severe disease, indicating a protective role for B cells. Mice transplanted with IL-10 KO B cells developed GVHD as severe as those receiving WT B cells. Besides that, mice transplanted with MHC II deficient B cells and as so, unable to present antigen to CD4+ T cells, developed as severe GVHD as animals transplanted without B cells. This result suggests that protection provided by mature naive B cells depends on antigen presentation and not IL-10 production by B cells. In the absence of donor B cells, transplanted mice exhibited disorganized lymphoid splenic tissue. Additionally, donor B cell depletion diminished the follicular T (Tfh)/T effector (Teff) ratio suggesting that protection was correlated with a shift to Tfh differentiation, reducing the number of effector T cells. Importantly, the Tfh/Teff shift impacts disease outcome since observed proinflammatory cytokine levels and tissue damage in target organs were consistent with disease protection. The role of transplanted B cells in the outcome of BMT and the development of acute GVHD should be carefully studied, since these cells are abundant in BMT products and are potent modulator and effector cells in allogeneic response. Extended Abstract Background: B cells are widely known for their ability to produce antibodies. In addition, B cells can act efficiently as antigen-presenting cells, implying the mutual regulation of both T and B lymphocyte subsets. T cell help for B cells has been known for more than 50 years; however, B cell help for T cells, especially regarding the modulation of follicular and regulatory phenotypes, had only lately been explored. Here, we studied the role of resting B cells in a model of systemic inflammatory disease mediated by T cells, graft-versus-host disease (GVHD), which is the main complication of allogeneic bone marrow transplantation. Objetive: The objective of this paper is to investigate the role of donor B cells in acute Graft-versus-Host Disease. STUDY DESIGN To investigate the role of donor B cells in aGVHD, we used a full MHC-mismatched bone marrow transplantation model. We infused C57BL/6 BM cells along with splenocytes depleted or not of B220+ cells into lethally irradiated BALB/c mice. We also used B cells from IL-10 KO mice to investigate the role of IL-10 produced by donor B cells and B cells from mice which cannot express MHC-II (CIITA KO) to investigate the role of cognate interaction between donor B and T cells. RESULTS Animals receiving transplants depleted of B cells presented a more severe disease, showing the existence of B cell-dependent protection. This protection was dependent on the T cell-B cell cognate interaction but not on IL-10 or Treg induction. In the absence of donor B cells, transplanted mice exhibited fewer GCs and a lower follicular T (Tfh)/T effector (Teff) ratio than mice transplanted in the presence of B cells. Protection was correlated with a shift to Tfh differentiation, reducing the number of effector cells. Importantly, the Tfh/Teff shift impacts disease outcome with less T cell-mediated disease due to more B cell-dependent Tfh generation with fewer effector T cells and lower proinflammatory cytokine levels detected in target organs. CONCLUSION We show that B-cell depleted bone marrow transplantation leads to a more severe disease, with earlier mortality related to increased organ damage. Such differences depend on cognate interactions between T cells and B cells, are IL-10 independent and are related to a shift in the differentiation of lymphocytes from the follicular helper phenotype to the effector phenotype. Therefore, Teffs, which are circulating cells, become relatively more numerous and can reach and damage the target tissues. These results point to caution in the early posttransplantation elimination of donor B cells. It is not a matter of eliminating only antibody-forming cells or cells that mediate Tfh generation but of B cells, which interact and modulate T cell activity, impacting a disease that is not antibody mediated.
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40
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Patel DA, Schroeder MA, Choi J, DiPersio JF. Mouse models of graft-versus-host disease. Methods Cell Biol 2022; 168:41-66. [DOI: 10.1016/bs.mcb.2021.12.008] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
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Braun LM, Zeiser R. Kinase Inhibition as Treatment for Acute and Chronic Graft- Versus-Host Disease. Front Immunol 2021; 12:760199. [PMID: 34868001 PMCID: PMC8635802 DOI: 10.3389/fimmu.2021.760199] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2021] [Accepted: 10/28/2021] [Indexed: 01/25/2023] Open
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HCT) is a potentially curative therapy for patients suffering from hematological malignancies via the donor immune system driven graft-versus-leukemia effect. However, the therapy is mainly limited by severe acute and chronic graft-versus-host disease (GvHD), both being life-threatening complications after allo-HCT. GvHD develops when donor T cells do not only recognize remaining tumor cells as foreign, but also the recipient’s tissue, leading to a severe inflammatory disease. Typical GvHD target organs include the skin, liver and intestinal tract. Currently all approved strategies for GvHD treatment are immunosuppressive therapies, with the first-line therapy being glucocorticoids. However, therapeutic options for glucocorticoid-refractory patients are still limited. Novel therapeutic approaches, which reduce GvHD severity while preserving GvL activity, are urgently needed. Targeting kinase activity with small molecule inhibitors has shown promising results in preclinical animal models and clinical trials. Well-studied kinase targets in GvHD include Rho-associated coiled-coil-containing kinase 2 (ROCK2), spleen tyrosine kinase (SYK), Bruton’s tyrosine kinase (BTK) and interleukin-2-inducible T-cell kinase (ITK) to control B- and T-cell activation in acute and chronic GvHD. Janus Kinase 1 (JAK1) and 2 (JAK2) are among the most intensively studied kinases in GvHD due to their importance in cytokine production and inflammatory cell activation and migration. Here, we discuss the role of kinase inhibition as novel treatment strategies for acute and chronic GvHD after allo-HCT.
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Affiliation(s)
- Lukas M Braun
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Faculty of Biology, University of Freiburg, Freiburg, Germany
| | - Robert Zeiser
- Department of Medicine I, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), University of Freiburg, Freiburg, Germany.,Centre for Biological Signalling Studies (BIOSS) and Centre for Integrative Biological Signalling Studies (CIBSS), University of Freiburg, Freiburg, Germany
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Tsuzuki H, Nagatsuka Y, Iwata M, Kitamura N, Nagasawa Y, Matsumoto T, Ito R, Takahashi T, Ito M, Nakamura H, Takei M. Antinuclear antibodies produced in HLA-DR transgenic humanized mice developed chronic graft-versus-host disease. Heliyon 2021; 7:e08380. [PMID: 34825089 PMCID: PMC8605287 DOI: 10.1016/j.heliyon.2021.e08380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Revised: 10/07/2021] [Accepted: 11/10/2021] [Indexed: 11/19/2022] Open
Abstract
Background Chronic graft versus host disease (GVHD) has been reported in humanized mice after the implantation of human hematopoietic stem cells (hu-HSC). As such, humanized mice have been applied to a mouse model of chronic GVHD; however, B-cell activation and autoantibody production did not occur, and the clinical features of chronic GVHD were not sufficiently reproduced. The purpose of this study was to establish an improved humanized mouse model with chronic GVHD using HLA-DR transgenic NOD/Shi-scid, IL-2RγKO (NOG) mice. Methods CD34-positive cells were isolated from blood extracted from HLA-DRB1∗0405-positive umbilical cords using magnetic cell isolation. Then these were transplanted into NOG-Iab KO, HLA-DR 0405 Tg mice aged 8–16 weeks. GVHD symptoms were observed 26 weeks after transplantation. Histological findings of the skin, lung, liver, and spleen were compared with those of non-humanized mice. Antinuclear antibodies (ANA) were measured by indirect immunofluorescence using sera isolated 26 weeks after transplantation. Results Although GVHD symptoms were not observed in humanized (hu-HSC) NOG-Iab KO, HLA-DR 0405 Tg mice during the observation period, histological findings of human T-cell infiltration were observed in the skin, liver, and lung, suggesting that GVDH was present; human tingible body macrophages or clusters of BCL-6-positive human B-cells were observed in the spleen. Furthermore, human IgG ANA with peripheral or homogeneous staining patterns were also detected in the sera. Conclusion Hu-HSC NOG-Iab KO, HLA-DR 0405 Tg mice differed from conventional models in terms of B-cell activation and ANA production. This study is the first to report on B-cell activation and autoantibody production in humanized mice with chronic GVHD, suggesting that hu-HSC NOG-Iab KO, HLA-DR 0405 Tg mice could be applied to a new humanized mouse model of chronic GVHD.
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Affiliation(s)
- Hiroshi Tsuzuki
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuko Nagatsuka
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Mitsuhiro Iwata
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Noboru Kitamura
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Yosuke Nagasawa
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Taro Matsumoto
- Division of Cell Regeneration and Transplantation, Department of Functional Morphology, Nihon University School of Medicine, Tokyo, Japan
| | - Ryoji Ito
- Central Institute for Experimental Animals, Kawasaki, Japan
| | | | - Mamoru Ito
- Central Institute for Experimental Animals, Kawasaki, Japan
| | - Hideki Nakamura
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
| | - Masami Takei
- Division of Hematology and Rheumatology, Department of Medicine, Nihon University School of Medicine, Tokyo, Japan
- Corresponding author.
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CXCL13 Is an Indicator of Germinal Center Activity and Alloantibody Formation Following Transplantation. Transplant Direct 2021; 7:e785. [PMID: 34778545 PMCID: PMC8580198 DOI: 10.1097/txd.0000000000001247] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 09/19/2021] [Indexed: 11/25/2022] Open
Abstract
Supplemental Digital Content is available in the text. Donor-specific antibodies (DSA) are a recognized cause of allograft injury, yet biomarkers that indicate their development posttransplant or guide management are not available. CXCL13 (chemokine [C-X-C motif] ligand 1) is a chemoattractant produced within secondary lymphoid organs necessary for germinal center (GC) and alloantibody formation. Perturbations in serum CXCL13 levels have been associated with humoral immune activity. Therefore, CXCL13 may correlate with the formation of HLA antibodies following transplantation.
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Choi HJ, Tang CHA, Tian L, Wu Y, Sofi MH, Ticer T, Schutt SD, Hu CCA, Yu XZ. XBP-1s Promotes B Cell Pathogenicity in Chronic GVHD by Restraining the Activity of Regulated IRE-1α-Dependent Decay. Front Immunol 2021; 12:705484. [PMID: 34659198 PMCID: PMC8517405 DOI: 10.3389/fimmu.2021.705484] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2021] [Accepted: 09/15/2021] [Indexed: 11/20/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapeutic procedure to treat hematological malignancies. However, the benefit of allo-HCT is limited by a major complication, chronic graft-versus-host disease (cGVHD). Since transmembrane and secretory proteins are generated and modified in the endoplasmic reticulum (ER), the ER stress response is of great importance to secretory cells including B cells. By using conditional knock-out (KO) of XBP-1, IRE-1α or both specifically on B cells, we demonstrated that the IRE-1α/XBP-1 pathway, one of the major ER stress response mediators, plays a critical role in B cell pathogenicity on the induction of cGVHD in murine models of allo-HCT. Endoribonuclease activity of IRE-1α activates XBP-1 signaling by converting unspliced XBP-1 (XBP-1u) mRNA into spliced XBP-1 (XBP-1s) mRNA but also cleaves other ER-associated mRNAs through regulated IRE-1α-dependent decay (RIDD). Further, ablation of XBP-1s production leads to unleashed activation of RIDD. Therefore, we hypothesized that RIDD plays an important role in B cells during cGVHD development. In this study, we found that the reduced pathogenicity of XBP-1 deficient B cells in cGVHD was reversed by RIDD restriction in IRE-1α kinase domain KO mice. Restraining RIDD activity per se in B cells resulted in an increased severity of cGVHD. Besides, inhibition of RIDD activity compromised B cell differentiation and led to dysregulated expression of MHC II and costimulatory molecules such as CD86, CD40, and ICOSL in B cells. Furthermore, restraining the RIDD activity without affecting XBP-1 splicing increased B cell ability to induce cGVHD after allo-HCT. These results suggest that RIDD is an important mediator for reducing cGVHD pathogenesis through targeting XBP-1s.
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Affiliation(s)
- Hee-Jin Choi
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Chih-Hang Anthony Tang
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, United States
| | - Linlu Tian
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Yongxia Wu
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - M Hanief Sofi
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Taylor Ticer
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Steven D Schutt
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States
| | - Chih-Chi Andrew Hu
- Center for Translational Research in Hematologic Malignancies, Houston Methodist Cancer Center, Houston Methodist Research Institute, Houston, TX, United States
| | - Xue-Zhong Yu
- Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, United States.,Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, United States
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Wolff D, Radojcic V, Lafyatis R, Cinar R, Rosenstein RK, Cowen EW, Cheng GS, Sheshadri A, Bergeron A, Williams KM, Todd JL, Teshima T, Cuvelier GDE, Holler E, McCurdy SR, Jenq RR, Hanash AM, Jacobsohn D, Santomasso BD, Jain S, Ogawa Y, Steven P, Luo ZK, Dietrich-Ntoukas T, Saban D, Bilic E, Penack O, Griffith LM, Cowden M, Martin PJ, Greinix HT, Sarantopoulos S, Socie G, Blazar BR, Pidala J, Kitko CL, Couriel DR, Cutler C, Schultz KR, Pavletic SZ, Lee SJ, Paczesny S. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IV. The 2020 Highly morbid forms report. Transplant Cell Ther 2021; 27:817-835. [PMID: 34217703 PMCID: PMC8478861 DOI: 10.1016/j.jtct.2021.06.001] [Citation(s) in RCA: 79] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/01/2021] [Indexed: 12/12/2022]
Abstract
Chronic graft-versus-host disease (GVHD) can be associated with significant morbidity, in part because of nonreversible fibrosis, which impacts physical functioning (eye, skin, lung manifestations) and mortality (lung, gastrointestinal manifestations). Progress in preventing severe morbidity and mortality associated with chronic GVHD is limited by a complex and incompletely understood disease biology and a lack of prognostic biomarkers. Likewise, treatment advances for highly morbid manifestations remain hindered by the absence of effective organ-specific approaches targeting "irreversible" fibrotic sequelae and difficulties in conducting clinical trials in a heterogeneous disease with small patient numbers. The purpose of this document is to identify current gaps, to outline a roadmap of research goals for highly morbid forms of chronic GVHD including advanced skin sclerosis, fasciitis, lung, ocular and gastrointestinal involvement, and to propose strategies for effective trial design. The working group made the following recommendations: (1) Phenotype chronic GVHD clinically and biologically in future cohorts, to describe the incidence, prognostic factors, mechanisms of organ damage, and clinical evolution of highly morbid conditions including long-term effects in children; (2) Conduct longitudinal multicenter studies with common definitions and research sample collections; (3) Develop new approaches for early identification and treatment of highly morbid forms of chronic GVHD, especially biologically targeted treatments, with a special focus on fibrotic changes; and (4) Establish primary endpoints for clinical trials addressing each highly morbid manifestation in relationship to the time point of intervention (early versus late). Alternative endpoints, such as lack of progression and improvement in physical functioning or quality of life, may be suitable for clinical trials in patients with highly morbid manifestations. Finally, new approaches for objective response assessment and exploration of novel trial designs for small populations are required.
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Affiliation(s)
- Daniel Wolff
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany.
| | - Vedran Radojcic
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Robert Lafyatis
- Division of Rheumatology and Clinical Immunology, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Resat Cinar
- Section on Fibrotic Disorders, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland
| | - Rachel K Rosenstein
- Center for Discovery and Innovation, Hackensack Meridian Health, Nutley, New Jersey
| | - Edward W Cowen
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland
| | - Guang-Shing Cheng
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Ajay Sheshadri
- Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anne Bergeron
- Department of Pulmonary Medicine, AP-HP Saint Louis Hospital & University of Paris, Paris, France
| | - Kirsten M Williams
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Jamie L Todd
- Division of Pulmonary, Allergy and Critical Care Medicine, Duke University, Durham, North Carolina
| | - Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Geoffrey D E Cuvelier
- Pediatric Blood and Marrow Transplant, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ernst Holler
- Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Shannon R McCurdy
- Division of Hematology/Oncology, Department of Medicine, Perelman School of Medicine of the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Robert R Jenq
- Departments of Genomic Medicine and Stem Cell Transplantation and Cellular Therapy, University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Alan M Hanash
- Departments of Medicine and Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York
| | - David Jacobsohn
- Children's National Hospital, George Washington University, Washington, District of Columbia
| | - Bianca D Santomasso
- Department of Neurology, Memorial Sloan Kettering Cancer Center, New York New York
| | - Sandeep Jain
- Department of Ophthalmology, University of Illinois Eye & Ear Infirmary, Chicago, Illinois
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Philipp Steven
- Division for Dry-Eye and ocular GvHD, Department of Ophthalmology, Medical Faculty and University Hospital, University of Cologne, Cologne, Germany
| | - Zhonghui Katie Luo
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, Massachusetts
| | - Tina Dietrich-Ntoukas
- Charité-Universitätsmedizin Berlin, corporate member of Freie Universität Berlin und Humboldt-Universität Berlin, Department of Ophthalmology, Berlin, Germany
| | - Daniel Saban
- Department of Ophthalmology and Department of Immunology, Duke University School of Medicine, Durham, North Carolina
| | - Ervina Bilic
- Department of Neurology, University of Zagreb School of Medicine, Zagreb, Croatia
| | - Olaf Penack
- Charité - Universitätsmedizin Berlin, corporate member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Department of Hematology, Oncology and Tumorimmunology, Berlin, Germany
| | - Linda M Griffith
- Division of Allergy Immunology and Transplantation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland
| | | | - Paul J Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | | | - Stefanie Sarantopoulos
- Division of Hematological Malignancies and Cellular Therapy, Duke University Department of Medicine, Duke Cancer Institute, Durham, North Carolina
| | - Gerard Socie
- Hematology Transplantation, AP-HP Saint Louis Hospital & University of Paris, Paris, France
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota
| | - Joseph Pidala
- Department of Blood and Marrow Transplantation and Cellular Immunotherapy. H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Carrie L Kitko
- Pediatric Stem Cell Transplant Program, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Daniel R Couriel
- Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Corey Cutler
- Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts
| | - Kirk R Schultz
- Pediatric Hematology/Oncology/BMT, BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Steven Z Pavletic
- Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Sophie Paczesny
- Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, South Carolina
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46
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Zhou X, Moore BB. Experimental Models of Infectious Pulmonary Complications Following Hematopoietic Cell Transplantation. Front Immunol 2021; 12:718603. [PMID: 34484223 PMCID: PMC8415416 DOI: 10.3389/fimmu.2021.718603] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 07/26/2021] [Indexed: 12/23/2022] Open
Abstract
Pulmonary infections remain a major cause of morbidity and mortality in hematopoietic cell transplantation (HCT) recipients. The prevalence and type of infection changes over time and is influenced by the course of immune reconstitution post-transplant. The interaction between pathogens and host immune responses is complex in HCT settings, since the conditioning regimens create periods of neutropenia and immunosuppressive drugs are often needed to prevent graft rejection and limit graft-versus-host disease (GVHD). Experimental murine models of transplantation are valuable tools for dissecting the procedure-related alterations to innate and adaptive immunity. Here we review mouse models of post-HCT infectious pulmonary complications, primarily focused on three groups of pathogens that frequently infect HCT recipients: bacteria (often P. aeruginosa), fungus (primarily Aspergillus fumigatus), and viruses (primarily herpesviruses). These mouse models have advanced our knowledge regarding how the conditioning and HCT process negatively impacts innate immunity and have provided new potential strategies of managing the infections. Studies using mouse models have also validated clinical observations suggesting that prior or occult infections are a potential etiology of noninfectious pulmonary complications post-HCT as well.
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Affiliation(s)
- Xiaofeng Zhou
- Dept. of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.,Division of Pulmonary and Critical Care Medicine, Dept. of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Bethany B Moore
- Dept. of Microbiology and Immunology, University of Michigan Medical School, Ann Arbor, MI, United States.,Division of Pulmonary and Critical Care Medicine, Dept. of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI, United States
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47
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Zanin-Zhorov A, Blazar BR. ROCK2, a critical regulator of immune modulation and fibrosis has emerged as a therapeutic target in chronic graft-versus-host disease. Clin Immunol 2021; 230:108823. [PMID: 34400321 PMCID: PMC8456981 DOI: 10.1016/j.clim.2021.108823] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 08/09/2021] [Accepted: 08/10/2021] [Indexed: 11/20/2022]
Abstract
Chronic graft-versus-host disease (cGVHD) is an immune-mediated disorder characterized by chronic inflammation and fibrosis. Rho-associated coiled-coil-containing protein kinases (ROCKs) are key coordinators of tissue response to injury, regulating multiple functions, such as gene expression and cell migration, proliferation and survival. Relevant to cGVHD and autoimmunity, only the ROCK2 isoform drives a pro-inflammatory type 17 helper T (Th17) cell response. Moreover, ROCK2 inhibition shifts the Th17/regulatory T (Treg) cell balance toward Treg cells and restores immune homeostasis in animal models of autoimmunity and cGVHD. Furthermore, the selective inhibition of ROCK2 by belumosudil reduces fibrosis by downregulating both transforming growth factor-β signaling and profibrotic gene expression, thereby impeding the creation of focal adhesions. Consistent with its anti-inflammatory and antifibrotic activities, belumosudil has demonstrated efficacy in clinical studies, resulting in an overall response rate of >70% in patients with cGVHD who failed 2 to 5 prior lines of systemic therapy. In summary, selective ROCK2 inhibition has emerged as a promising novel therapeutic approach for treating cGVHD and other immunologic diseases with unique mechanisms of action, targeting both immune imbalance and detrimental fibrotic responses.
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Affiliation(s)
| | - Bruce R Blazar
- University of Minnesota Cancer Center and Department of Pediatrics, Division of Blood & Marrow Transplant & Cellular Therapy, Minneapolis, MN 55455, USA.
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48
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Cieri N, Maurer K, Wu CJ. 60 Years Young: The Evolving Role of Allogeneic Hematopoietic Stem Cell Transplantation in Cancer Immunotherapy. Cancer Res 2021; 81:4373-4384. [PMID: 34108142 PMCID: PMC8416782 DOI: 10.1158/0008-5472.can-21-0301] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 04/27/2021] [Accepted: 06/07/2021] [Indexed: 12/30/2022]
Abstract
The year 2020 marked the 30th anniversary of the Nobel Prize in Medicine awarded to E. Donnall Thomas for the development of allogeneic hematopoietic stem cell transplantation (allo-HSCT) to treat hematologic malignancies and other blood disorders. Dr. Thomas, "father of bone marrow transplantation," first developed and reported this technique in 1957, and in the ensuing decades, this seminal study has impacted fundamental work in hematology and cancer research, including advances in hematopoiesis, stem cell biology, tumor immunology, and T-cell biology. As the first example of cancer immunotherapy, understanding the mechanisms of antitumor biology associated with allo-HSCT has given rise to many of the principles used today in the development and implementation of novel transformative immunotherapies. Here we review the historical basis underpinning the development of allo-HSCT as well as advances in knowledge obtained by defining mechanisms of allo-HSCT activity. We review how these principles have been translated to novel immunotherapies currently utilized in clinical practice and describe potential future applications for allo-HSCT in cancer research and development of novel therapeutic strategies.
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Affiliation(s)
- Nicoletta Cieri
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Katie Maurer
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
| | - Catherine J Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts.
- Broad Institute of Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts
- Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts
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49
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Teshima T, Hill GR. The Pathophysiology and Treatment of Graft- Versus-Host Disease: Lessons Learnt From Animal Models. Front Immunol 2021; 12:715424. [PMID: 34489966 PMCID: PMC8417310 DOI: 10.3389/fimmu.2021.715424] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/26/2021] [Indexed: 12/11/2022] Open
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a curative treatment for hematologic malignancies, bone marrow failure syndromes, and inherited immunodeficiencies and metabolic diseases. Graft-versus-host disease (GVHD) is the major life-threatening complication after allogeneic HCT. New insights into the pathophysiology of GVHD garnered from our understanding of the immunological pathways within animal models have been pivotal in driving new therapeutic paradigms in the clinic. Successful clinical translations include histocompatibility matching, GVHD prophylaxis using cyclosporine and methotrexate, posttransplant cyclophosphamide, and the use of broad kinase inhibitors that inhibit cytokine signaling (e.g. ruxolitinib). New approaches focus on naïve T cell depletion, targeted cytokine modulation and the inhibition of co-stimulation. This review highlights the use of animal transplantation models to guide new therapeutic principles.
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Affiliation(s)
- Takanori Teshima
- Department of Hematology, Hokkaido University Faculty of Medicine, Sapporo, Japan
| | - Geoffrey R. Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
- Division of Medical Oncology, The University of Washington, Seattle, WA, United States
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50
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Pulmonary Complications of Pediatric Hematopoietic Cell Transplantation. A National Institutes of Health Workshop Summary. Ann Am Thorac Soc 2021; 18:381-394. [PMID: 33058742 DOI: 10.1513/annalsats.202001-006ot] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Approximately 2,500 pediatric hematopoietic cell transplants (HCTs), most of which are allogeneic, are performed annually in the United States for life-threatening malignant and nonmalignant conditions. Although HCT is undertaken with curative intent, post-HCT complications limit successful outcomes, with pulmonary dysfunction representing the leading cause of nonrelapse mortality. To better understand, predict, prevent, and/or treat pulmonary complications after HCT, a multidisciplinary group of 33 experts met in a 2-day National Institutes of Health Workshop to identify knowledge gaps and research strategies most likely to improve outcomes. This summary of Workshop deliberations outlines the consensus focus areas for future research.
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