|
1
|
Boiko JR, Ensbey KS, Waltner OG, Jenkins IC, Bhise SS, MacDonald KPA, Blazar BR, Hall AM, Gooley TA, Minnie SA, Lee SJ, Furlan SN, Hill GR. Defining pathogenic IL-17 and CSF-1 gene expression signatures in chronic graft-versus-host disease. Blood 2025; 145:2214-2228. [PMID: 39977705 DOI: 10.1182/blood.2024025337] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2024] [Revised: 01/23/2025] [Accepted: 01/23/2025] [Indexed: 02/22/2025] Open
Abstract
ABSTRACT Chronic graft-versus-host disease (cGVHD) remains the leading cause of nonrelapse morbidity and mortality after allogeneic hematopoietic cell transplantation (HCT). Effective therapeutic agents targeting dysregulated cytokines including interleukin-17 (IL-17) and colony-stimulating factor 1 (CSF-1) have been defined in preclinical models of cGVHD, and efficacy in subsequent clinical trials has led to their recent US Food and Drug Administration approval. Despite this, these agents are effective in only a subset of patients, expensive, difficult to access outside the United States, and used in a trial-and-error fashion. The ability to readily discern druggable, dysregulated immunity in these patients is desperately needed to facilitate the selection of appropriate treatment and to potentially identify high-risk individuals for preemptive therapy. We used single-cell sequencing-based approaches in our informative preclinical cGVHD models to "reverse engineer" temporal IL-17 and CSF-1 signatures in mouse blood that could be used to interrogate patients. We defined distinct, nonintuitive IL-17 and CSF-1 signatures in mouse blood monocytes that could be identified in relevant monocyte populations within 70% of patients at diagnosis of cGVHD and in half of patients at day +100 after HCT who subsequently developed cGVHD. These signatures can now be evaluated prospectively in clinical studies to help delineate potential responder and nonresponders to relevant therapeutics targeting these pathways.
Collapse
Affiliation(s)
- Julie R Boiko
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Pediatrics, University of Washington, Seattle, WA
| | - Kathleen S Ensbey
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Olivia G Waltner
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Isaac C Jenkins
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Shruti S Bhise
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Kelli P A MacDonald
- Department of Infection and Inflammation, Queensland Institute of Medical Research Berghofer, Brisbane, Australia
| | - Bruce R Blazar
- Division of Blood and Marrow Transplant and Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, MN
| | - A Marcie Hall
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Ted A Gooley
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Simone A Minnie
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, WA
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Center, Seattle, WA
- Department of Medicine, University of Washington, Seattle, WA
| | - Scott N Furlan
- 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
| |
Collapse
|
|
2
|
Raoufi A, Soleimani Samarkhazan H, Nouri S, Khaksari MN, Abbasi Sourki P, Sargazi Aval O, Baradaran B, Aghaei M. Macrophages in graft-versus-host disease (GVHD): dual roles as therapeutic tools and targets. Clin Exp Med 2025; 25:73. [PMID: 40048037 PMCID: PMC11885342 DOI: 10.1007/s10238-025-01588-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Accepted: 02/03/2025] [Indexed: 03/09/2025]
Abstract
Graft-versus-host disease remains one of the most formidable barriers to the complete success of hematopoietic stem cell transplantation that has emerged as the curative approach for many hematopoietic malignancies because it affects quality of life and overall survival. Macrophages are among the important members of the immune system, which perform dual roles in GVHD as both therapeutic tools and targets. This review epitomizes the multifunctional role of macrophages in the pathophysiology of both acute and chronic GVHD. Macrophages play an important role in the early phase of GVHD because of their recruitment and infiltration into target organs. Furthermore, they polarize into two functionally different phenotypes, including M1 and M2. In the case of acute GVHD, most macrophages express the M1 phenotype characterized by the production of pro-inflammatory cytokines that contribute to tissue damage. In contrast, in chronic GVHD, macrophages tend toward the M2 phenotype associated with the repair of tissues and fibrosis. A critical balance among these phenotypes is central to the course and severity of GVHD. Further interactions of macrophages with other lymphocytes such as T cells, B cells, and fibroblast further determine the course of GVHD. Macrophage interaction associated with alloreactive T cells promotes inflammation. This is therefore important in inducing injuries of tissues during acute GVHD. Interaction of macrophages, B cell, fibroblast, and CD4+ T cells promotes fibrosis during chronic GVHD and, hence, the subsequent dysfunction of organs. These are some insights, while several challenges remain. First, the impact of the dominant cytokines in GVHD on the polarization of macrophages is incompletely characterized and sometimes controversial. Second, the development of targeted therapies able to modulate macrophage function without systemic side effects remains an area of ongoing investigation. Future directions involve the exploration of macrophage-targeted therapies, including small molecules, antibodies, and nanotechnology, which modulate macrophage behavior and improve patient outcomes. This underlines the fact that a profound understanding of the dual role of macrophages in GVHD is essential for developing new and more effective therapeutic strategies. Targeting macrophages might represent one avenue for decreasing the incidence and severity of GVHD and improving the success and safety of HSCT.
Collapse
Affiliation(s)
- Atieh Raoufi
- Department of Immunology, Student Research Committee, School of Medicine, Zanjan University of Medical Science, Zanjan, Iran
| | - Hamed Soleimani Samarkhazan
- Student Research Committee, Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Nouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Science, Tabriz, Iran
| | - Mohammad Navid Khaksari
- Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
- Student Research Committee, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Parvaneh Abbasi Sourki
- Department of Hematology, Faculty of Medical Science, Tarbiat Modares University, Tehran, Iran
| | - Omolbanin Sargazi Aval
- Department of Hematology, Faculty of Allied Medical Sciences, Zabol University of Medical Sciences, Zabol, Iran
| | - Behzad Baradaran
- Immunology Research Center, Tabriz University of Medical Sciences, Daneshghah Ave, Tabriz, Iran.
| | - Mojtaba Aghaei
- Student Research Committee, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
- Thalassemia & Hemoglobinopathy Research Center, Health Research Institute, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran.
| |
Collapse
|
|
3
|
Takahashi H, Yamaguchi N, Okayama N, Nishioka M, Mahbub MH, Hase R, Suehiro Y, Yamasaki T, Takahashi S, Tojo A, Tanabe T. Relationship Between an Interleukin 6 SNP and Relapse After Allogeneic Bone Marrow Transplantation. J Clin Med 2025; 14:476. [PMID: 39860482 PMCID: PMC11765773 DOI: 10.3390/jcm14020476] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Revised: 12/24/2024] [Accepted: 01/07/2025] [Indexed: 01/27/2025] Open
Abstract
Background/Objectives: Unrelated bone marrow transplantation (BMT) is a curative treatment for hematological malignancies. While HLA mismatch is a recognized risk factor in unrelated BMT, the significance of non-HLA single nucleotide polymorphisms (SNPs) remains uncertain. Cytokines play key roles in several aspects of unrelated BMT. Although the relationship between cytokine gene SNPs and BMT outcomes has been examined, the findings obtained have been inconsistent; therefore, further investigations in additional cohorts are warranted. Methods: Four SNPs in the IL2, IL6, IFN-gamma, and TGF-beta1 genes were retrospectively genotyped in 822 malignant patients and their corresponding donors who received unrelated BMT through the Japan Marrow Donor Program with compatibility at minimum HLA-A, -B, and -DRB1. The relationships between these SNP genotypes and BMT outcomes were statistically analyzed. Results: The donor interleukin-6 (IL6) SNP, rs1800796, also known as -572G>C and -634C/G, was associated with the relapse of the original disease in both univariable and multivariable regression analyses (minimum p-value = 0.0013), and the cumulative incidence curve analysis identified CC as a risk genotype (p-value = 0.0012). None of these SNPs correlated with overall survival. Conclusions: The donor IL6 SNP, rs1800796, may serve as a useful predictor of tumor relapses if validated.
Collapse
Affiliation(s)
- Hidekazu Takahashi
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan; (H.T.); (N.Y.); (M.H.M.); (R.H.)
| | - Natsu Yamaguchi
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan; (H.T.); (N.Y.); (M.H.M.); (R.H.)
| | - Naoko Okayama
- Division of Laboratory, Yamaguchi University Hospital, Ube 755-8505, Japan; (N.O.); (M.N.); (Y.S.); (T.Y.)
- Division of Medical Genetics, Yamaguchi University Hospital, Ube 755-8505, Japan
| | - Mitsuaki Nishioka
- Division of Laboratory, Yamaguchi University Hospital, Ube 755-8505, Japan; (N.O.); (M.N.); (Y.S.); (T.Y.)
| | - M. H. Mahbub
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan; (H.T.); (N.Y.); (M.H.M.); (R.H.)
| | - Ryosuke Hase
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan; (H.T.); (N.Y.); (M.H.M.); (R.H.)
| | - Yutaka Suehiro
- Division of Laboratory, Yamaguchi University Hospital, Ube 755-8505, Japan; (N.O.); (M.N.); (Y.S.); (T.Y.)
- Division of Medical Genetics, Yamaguchi University Hospital, Ube 755-8505, Japan
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
| | - Takahiro Yamasaki
- Division of Laboratory, Yamaguchi University Hospital, Ube 755-8505, Japan; (N.O.); (M.N.); (Y.S.); (T.Y.)
- Department of Oncology and Laboratory Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan
| | - Satoshi Takahashi
- Division of Clinical Precision Research Platform, The Institute of Medical Science, The University of Tokyo, Tokyo 113-8654, Japan;
| | - Arinobu Tojo
- Tokyo Medical and Dental University, Tokyo 113-8510, Japan;
| | - Tsuyoshi Tanabe
- Department of Public Health and Preventive Medicine, Yamaguchi University Graduate School of Medicine, Ube 755-8505, Japan; (H.T.); (N.Y.); (M.H.M.); (R.H.)
| |
Collapse
|
|
4
|
Sato S, Ogawa Y, Asai K, Shimizu E, Shimizu S, Taniguchi H, Okazaki T, Shimmura S, Negishi K, Hirayama M. Exploratory study on the efficacy of topical pan-JAK inhibitor in ocular and skin GVHD in a sclerodermatous GVHD mouse model. Sci Rep 2025; 15:532. [PMID: 39748084 PMCID: PMC11696563 DOI: 10.1038/s41598-024-84380-6] [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: 04/11/2024] [Accepted: 12/23/2024] [Indexed: 01/04/2025] Open
Abstract
Systemic administration of Janus kinase (JAK) inhibitors is effective in treating chronic graft-versus-host disease (cGVHD) but is associated with side effects. Topical drug administration effectively minimizes side effects. We aimed to investigate potential trends of the efficacy of topical delgocitinib administration in a mouse model. Allogenic bone-marrow transplantation (BMT) was performed from B10.D2. to BALB/c mice, leading to sclerodermatous GVHD. GVHD mice were treated with delgocitinib eye drops or ointment with samples analyzed at 4 weeks post-BMT. Topical delgocitinib ointment and eye-drop administration significantly increased the meibomian gland (MG) area and attenuated corneal epithelial damage. Pathological and immunohistochemical analyses revealed a substantial reduction in inflammation and pathological fibrosis of the skin and eyelids in delgocitinib-treated GVHD mice. Signal transducer and activator of transcription (STAT)1, STAT3, and STAT5A phosphorylation was significantly increased in the back skin and eyelids of vehicle-treated GVHD mice; topical delgocitinib administration significantly reduced the expression of these phosphorylated STAT molecules. Delgocitinib eye drops significantly attenuated corneal epithelial damage, MG acinar depletion, and inflammatory cells infiltration in GVHD mouse corneas. The JAK/STAT signaling pathway was significantly upregulated in GVHD mice. In summary, our data suggested that topical delgocitinib administration had the potential to attenuate cGVHD phenotype severity in the skin and eyes of sclerodermatous GVHD mice.
Collapse
Affiliation(s)
- Shinri Sato
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan.
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan.
| | - Kazuki Asai
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| | - Eisuke Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| | - Shota Shimizu
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| | - Hiroko Taniguchi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| | - Takahiro Okazaki
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| | - Shigeto Shimmura
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
- Fujita Medical Innovation Center Tokyo, Fujita Health University, Tokyo, Japan
| | - Kazuno Negishi
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| | - Masatoshi Hirayama
- Department of Ophthalmology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-0016, Japan
| |
Collapse
|
|
5
|
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.
Collapse
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
| |
Collapse
|
|
6
|
Canichella M, de Fabritiis P. Pulmonary GvHD: is it time to change the NIH diagnostic criteria? Clin Hematol Int 2024; 6:69-73. [PMID: 39440225 PMCID: PMC11494443 DOI: 10.46989/001c.124551] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Accepted: 08/27/2024] [Indexed: 10/25/2024] Open
|
|
7
|
Armstrong A, Tang Y, Mukherjee N, Zhang N, Huang G. Into the storm: the imbalance in the yin-yang immune response as the commonality of cytokine storm syndromes. Front Immunol 2024; 15:1448201. [PMID: 39318634 PMCID: PMC11420043 DOI: 10.3389/fimmu.2024.1448201] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Accepted: 08/22/2024] [Indexed: 09/26/2024] Open
Abstract
There is a continuous cycle of activation and contraction in the immune response against pathogens and other threats to human health in life. This intrinsic yin-yang of the immune response ensures that inflammatory processes can be appropriately controlled once that threat has been resolved, preventing unnecessary tissue and organ damage. Various factors may contribute to a state of perpetual immune activation, leading to a failure to undergo immune contraction and development of cytokine storm syndromes. A literature review was performed to consider how the trajectory of the immune response in certain individuals leads to cytokine storm, hyperinflammation, and multiorgan damage seen in cytokine storm syndromes. The goal of this review is to evaluate how underlying factors contribute to cytokine storm syndromes, as well as the symptomatology, pathology, and long-term implications of these conditions. Although the recognition of cytokine storm syndromes allows for universal treatment with steroids, this therapy shows limitations for symptom resolution and survival. By identifying cytokine storm syndromes as a continuum of disease, this will allow for a thorough evaluation of disease pathogenesis, consideration of targeted therapies, and eventual restoration of the balance in the yin-yang immune response.
Collapse
Affiliation(s)
- Amy Armstrong
- Department of Cell Systems and Anatomy, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
- Department of Microbiology, Immunology, and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Yuting Tang
- Division of Experimental Hematology and Cancer Biology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States
| | - Neelam Mukherjee
- Department of Microbiology, Immunology, and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
- Department of Urology, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Nu Zhang
- Department of Microbiology, Immunology, and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Gang Huang
- Department of Cell Systems and Anatomy, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
- Department of Microbiology, Immunology, and Molecular Genetics, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
- Department of Pathology & Laboratory Medicine, Long School of Medicine, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| |
Collapse
|
|
8
|
Dou Y, Nian Z, Wang D, Sun G, Zhou L, Hu Z, Ke J, Zhu X, Sun R, Tian Z, Fu B, Zhou Y, Wei H. Reconstituted CD74 + NK cells trigger chronic graft versus host disease after allogeneic bone marrow transplantation. J Autoimmun 2024; 147:103274. [PMID: 38936148 DOI: 10.1016/j.jaut.2024.103274] [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: 02/02/2024] [Revised: 05/27/2024] [Accepted: 06/18/2024] [Indexed: 06/29/2024]
Abstract
Chronic graft-versus-host disease (cGVHD) is the most common long-term complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The patients with pulmonary cGVHD in particular have a very poor prognosis. NK cells are the first reconstituted lymphocyte subset after allo-HSCT; however, the impact of reconstituted NK cells on cGVHD is unclear. Here, we found allogeneic recipients showed obvious pulmonary cGVHD. Surprisingly, deletion of reconstituted NK cells resulted in maximal relief of pulmonary cGVHD. Mechanistically, reconstituted NK cells with donor profiles modulated the pulmonary inflammatory microenvironment to trigger cGVHD. Reconstituted NK cells secreted IFN-γ and TNF-α to induce CXCL10 production by epithelial cells, which recruited macrophages and CD4+ T cells to the lungs. Then macrophages and CD4+ T cells were activated by the inflammatory microenvironment, thereby mediating lung injury. Through assessment of differences in cellular energy, we found that CD74+ NK cells with high mitochondrial potential and pro-inflammatory activity triggered pulmonary cGVHD. Furthermore, targeted elimination of CD74+ NK cells using the anti-CD74 antibody significantly alleviated pulmonary cGVHD but preserved the CD74- NK cells to exert graft-versus-leukemia (GVL) effects. Data from human samples corroborated our findings in mouse models. Collectively, our results reveal that reconstituted CD74+ NK cells trigger pulmonary cGVHD and suggest that administration of CD74 antibody was a potential therapeutic for patients with cGVHD.
Collapse
Affiliation(s)
- Yingchao Dou
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zhigang Nian
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Dongyao Wang
- Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China; Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Guangyu Sun
- Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China; Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Li Zhou
- Department of Hematology, The Second Affiliated Hospital of Anhui Medical University, Hefei, China
| | - Ziming Hu
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Jieqi Ke
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Xiaoyu Zhu
- Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China; Blood and Cell Therapy Institute, Anhui Provincial Key Laboratory of Blood Research and Applications, University of Science and Technology of China, Hefei, Anhui, 230027, China
| | - Rui Sun
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Zhigang Tian
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China
| | - Binqing Fu
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China.
| | - Yonggang Zhou
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China.
| | - Haiming Wei
- Key Laboratory of Immune Response and Immunotherapy, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Institute of Immunology, University of Science and Technology of China, Hefei, China.
| |
Collapse
|
|
9
|
Wang Y, Ullah MA, Waltner OG, Bhise SS, Ensbey KS, Schmidt CR, Legg SR, Sekiguchi T, Nelson EL, Kuns RD, Nemychenkov NS, Atilla E, Yeh AC, Takahashi S, Boiko JR, Varelias A, Blazar BR, Koyama M, Minnie SA, Clouston AD, Furlan SN, Zhang P, Hill GR. Calcineurin inhibition rescues alloantigen-specific central memory T cell subsets that promote chronic GVHD. J Clin Invest 2024; 134:e170125. [PMID: 38828727 PMCID: PMC11142741 DOI: 10.1172/jci170125] [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: 03/02/2023] [Accepted: 04/09/2024] [Indexed: 06/05/2024] Open
Abstract
Calcineurin inhibitors (CNIs) constitute the backbone of modern acute graft-versus-host disease (aGVHD) prophylaxis regimens but have limited efficacy in the prevention and treatment of chronic GVHD (cGVHD). We investigated the effect of CNIs on immune tolerance after stem cell transplantation with discovery-based single-cell gene expression and T cell receptor (TCR) assays of clonal immunity in tandem with traditional protein-based approaches and preclinical modeling. While cyclosporin and tacrolimus suppressed the clonal expansion of CD8+ T cells during GVHD, alloreactive CD4+ T cell clusters were preferentially expanded. Moreover, CNIs mediated reversible dose-dependent suppression of T cell activation and all stages of donor T cell exhaustion. Critically, CNIs promoted the expansion of both polyclonal and TCR-specific alloreactive central memory CD4+ T cells (TCM) with high self-renewal capacity that mediated cGVHD following drug withdrawal. In contrast to posttransplant cyclophosphamide (PT-Cy), CSA was ineffective in eliminating IL-17A-secreting alloreactive T cell clones that play an important role in the pathogenesis of cGVHD. Collectively, we have shown that, although CNIs attenuate aGVHD, they paradoxically rescue alloantigen-specific TCM, especially within the CD4+ compartment in lymphoid and GVHD target tissues, thus predisposing patients to cGVHD. These data provide further evidence to caution against CNI-based immune suppression without concurrent approaches that eliminate alloreactive T cell clones.
Collapse
Affiliation(s)
- Yewei Wang
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Hematology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Md Ashik Ullah
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Olivia G. Waltner
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Shruti S. Bhise
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Kathleen S. Ensbey
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Christine R. Schmidt
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Samuel R.W. Legg
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Tomoko Sekiguchi
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Ethan L. Nelson
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Rachel D. Kuns
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
| | - Nicole S. Nemychenkov
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Erden Atilla
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Albert C. Yeh
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Shuichiro Takahashi
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Julie R. Boiko
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Antiopi Varelias
- QIMR Berghofer Medical Research Institute, Herston, Queensland, Australia
- Faculty of Medicine, The University of Queensland, Brisbane, Queensland, Australia
| | - Bruce R. Blazar
- Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota, USA
| | - Motoko Koyama
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Simone A. Minnie
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | | | - Scott N. Furlan
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Department of Pediatrics and
| | - Ping Zhang
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
| | - Geoffrey R. Hill
- Translational Science and Therapeutics Division, Fred Hutchinson Cancer Center, Seattle, Washington, USA
- Division of Medical Oncology, University of Washington, Seattle, Washington, USA
| |
Collapse
|
|
10
|
Rosenstein RK, Rose JJ, Brooks SR, Tsai WL, Gadina M, Pavletic SZ, Nagao K, Cowen EW. Identification of Fibroinflammatory and Fibrotic Transcriptomic Subsets of Human Cutaneous Sclerotic Chronic Graft-Versus-Host Disease. JID INNOVATIONS 2024; 4:100246. [PMID: 38357212 PMCID: PMC10864809 DOI: 10.1016/j.xjidi.2023.100246] [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: 12/14/2022] [Revised: 10/23/2023] [Accepted: 11/06/2023] [Indexed: 02/16/2024] Open
Abstract
Cutaneous sclerotic chronic graft-versus-host disease (cGVHD) is a common and highly morbid complication of allogeneic hematopoietic stem cell transplantation. Our goals were to identify signals active in the skin of patients with sclerotic cGVHD in an effort to better understand how to treat this manifestation and to explore the heterogeneity of the disease. We identified genes that are significantly upregulated in the skin of patients with sclerotic cGVHD (n = 17) compared with those in the skin of patients who underwent allogeneic hematopoietic stem cell transplantation without cutaneous cGVHD (n = 9) by bulk RNA sequencing. Sclerotic cGVHD was most associated with T helper 1, phagocytic, and fibrotic pathways. In addition, different transcriptomic groups of affected patients were discovered: those with fibrotic and inflammatory/T helper 1 gene expression (the fibroinflammatory group) and those with predominantly fibrotic/TGFβ-associated expression (the fibrotic group). Further study will help elucidate whether these gene expression findings can be used to tailor treatment decisions. Multiple proteins encoded by highly induced genes in the skin (SFRP4, SERPINE2, COMP) were also highly induced in the plasma of patients with sclerotic cGVHD (n = 16) compared with those in plasma of control patients who underwent allogeneic hematopoietic stem cell transplantation without sclerotic cGVHD (n = 17), suggesting these TGFβ and Wnt pathway mediators as candidate blood biomarkers of the disease.
Collapse
Affiliation(s)
- Rachel K. Rosenstein
- Center for Discovery and Innovation, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA
- Department of Medicine, Hackensack University Medical Center, Hackensack Meridian School of Medicine, Nutley, New Jersey, USA
| | | | - Stephen R. Brooks
- Biodata Mining and Discovery Section, Office of Science and Technology, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Wanxia L. Tsai
- Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Massimo Gadina
- Translational Immunology Section, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Steven Z. Pavletic
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA
| | - Keisuke Nagao
- Cutaneous Leukocyte Biology Section, Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| | - Edward W. Cowen
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland, USA
| |
Collapse
|
|
11
|
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.
Collapse
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.
| |
Collapse
|
|
12
|
Abstract
ABSTRACT Inflammation is a major underlying mechanism in the progression of numerous cardiovascular diseases (CVDs). Regulatory T cells (Tregs) are typical immune regulatory cells with recognized immunosuppressive properties. Despite the immunosuppressive properties, researchers have acknowledged the significance of Tregs in maintaining tissue homeostasis and facilitating repair/regeneration. Previous studies unveiled the heterogeneity of Tregs in the heart and aorta, which expanded in CVDs with unique transcriptional phenotypes and reparative/regenerative function. This review briefly summarizes the functional principles of Tregs, also including the synergistic effect of Tregs and other immune cells in CVDs. We discriminate the roles and therapeutic potential of Tregs in CVDs such as atherosclerosis, hypertension, abdominal arterial aneurysm, pulmonary arterial hypertension, Kawasaki disease, myocarditis, myocardial infarction, and heart failure. Tregs not only exert anti-inflammatory effects but also actively promote myocardial regeneration and vascular repair, maintaining the stability of the local microenvironment. Given that the specific mechanism of Tregs functioning in CVDs remains unclear, we reviewed previous clinical and basic studies and the latest findings on the function and mechanism of Tregs in CVDs.
Collapse
Affiliation(s)
- Wangling Hu
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Jingyong Li
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| | - Xiang Cheng
- Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
- Hubei Engineering Research Center for Immunological Diagnosis and Therapy of Cardiovascular Diseases, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430022, China
| |
Collapse
|
|
13
|
Haroun E, Agrawal K, Leibovitch J, Kassab J, Zoghbi M, Dutta D, Lim SH. Chronic graft-versus-host disease in pediatric patients: Differences and challenges. Blood Rev 2023; 60:101054. [PMID: 36805299 DOI: 10.1016/j.blre.2023.101054] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2022] [Revised: 01/31/2023] [Accepted: 02/02/2023] [Indexed: 02/10/2023]
Abstract
Despite the use of high-resolution molecular techniques for tissue typing, chronic graft-versus-host disease (cGVHD) remains a major complication following allogeneic hematopoietic stem cell transplant. cGVHD adversely affects the life-expectancy and quality of life. The latter is particularly important and functionally relevant in pediatric patients who have a longer life-expectancy than adults. Current laboratory evidence suggests that there is not any difference in the pathophysiology of cGVHD between adults and pediatric patients. However, there are some clinical features and complications of the disease that are different in pediatric patients. There are also challenges in the development of new therapeutics for this group of patients. In this review, we will discuss the epidemiology, pathophysiology, clinical features and consequences of the disease, and highlight the differences between pediatric and adult patients. We will examine the current treatment options for pediatric patients with moderate to severe cGVHD and discuss the challenges facing therapeutic development for cGVHD in the pediatric population.
Collapse
Affiliation(s)
- Elio Haroun
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Kavita Agrawal
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Jennifer Leibovitch
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Joseph Kassab
- Department of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Marianne Zoghbi
- Department of Medicine, Saint-Joseph University of Beirut, Beirut, Lebanon
| | - Dibyendu Dutta
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America
| | - Seah H Lim
- Division of Hematology and Oncology, State University of New York Upstate Medical University, Syracuse, NY, United States of America,; Sanofi Oncology, Cambridge, MA, United States of America.
| |
Collapse
|
|
14
|
Raman D, Chêne C, Nicco C, Jeljeli M, Eu JQ, Clément MV, Batteux F, Pervaiz S. Therapeutic Potential of a Senolytic Approach in a Murine Model of Chronic GVHD. BIOLOGY 2023; 12:biology12050647. [PMID: 37237461 DOI: 10.3390/biology12050647] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 04/07/2023] [Accepted: 04/18/2023] [Indexed: 05/28/2023]
Abstract
Graft-versus-host disease (GVHD) is a life-threatening systemic complication of allogeneic hematopoietic stem cell transplantation (HSCT) characterized by dysregulation of T and B cell activation and function, scleroderma-like features, and multi-organ pathology. The treatment of cGVHD is limited to the management of symptoms and long-term use of immunosuppressive therapy, which underscores the need for developing novel treatment approaches. Notably, there is a striking similarity between cytokines/chemokines responsible for multi-organ damage in cGVHD and pro-inflammatory factors, immune modulators, and growth factors secreted by senescent cells upon the acquisition of senescence-associated secretory phenotype (SASP). In this pilot study, we questioned the involvement of senescent cell-derived factors in the pathogenesis of cGVHD triggered upon allogeneic transplantation in an irradiated host. Using a murine model that recapitulates sclerodermatous cGVHD, we investigated the therapeutic efficacy of a senolytic combination of dasatinib and quercetin (DQ) administered after 10 days of allogeneic transplantation and given every 7 days for 35 days. Treatment with DQ resulted in a significant improvement in several physical and tissue-specific features, such as alopecia and earlobe thickness, associated with cGVHD pathogenesis in allograft recipients. DQ also mitigated cGVHD-associated changes in the peripheral T cell pool and serum levels of SASP-like cytokines, such as IL-4, IL-6 and IL-8Rα. Our results support the involvement of senescent cells in the pathogenesis of cGVHD and provide a rationale for the use of DQ, a clinically approved senolytic approach, as a potential therapeutic strategy.
Collapse
Affiliation(s)
- Deepika Raman
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
| | - Charlotte Chêne
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, 75014 Paris, France
| | - Carole Nicco
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, 75014 Paris, France
| | - Mohamed Jeljeli
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, 75014 Paris, France
- Université de Paris, Faculté de Médecine, AP-HP-Centre Université de Paris, Hôpital Cochin, Service d'Immunologie Biologique, 75014 Paris, France
| | - Jie Qing Eu
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- Cancer Science Institute, National University of Singapore, Singapore 117597, Singapore
| | - Marie-Véronique Clément
- Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- NUS Medicine Healthy Longevity Program, National University of Singapore, Singapore 117597, Singapore
- Integrated Science and Engineering Program, NUS Graduate School, National University of Singapore, Singapore 117597, Singapore
| | - Frédéric Batteux
- Département 3I, Infection, Immunité et Inflammation, Institut Cochin, INSERM U1016, Université de Paris, 75014 Paris, France
- Université de Paris, Faculté de Médecine, AP-HP-Centre Université de Paris, Hôpital Cochin, Service d'Immunologie Biologique, 75014 Paris, France
| | - Shazib Pervaiz
- Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- NUS Medicine Healthy Longevity Program, National University of Singapore, Singapore 117597, Singapore
- Integrated Science and Engineering Program, NUS Graduate School, National University of Singapore, Singapore 117597, Singapore
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore
- National University Cancer Institute, National University Health System, Singapore 117597, Singapore
| |
Collapse
|
|
15
|
Kloehn J, Kruchen A, Schütze K, Wustrau K, Schrum J, Müller I. Immune Ablation and Stem Cell Rescue in Two Pediatric Patients with Progressive Severe Chronic Graft-Versus-Host Disease. Int J Mol Sci 2022; 23:ijms232315403. [PMID: 36499733 PMCID: PMC9735744 DOI: 10.3390/ijms232315403] [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: 10/28/2022] [Revised: 11/29/2022] [Accepted: 12/03/2022] [Indexed: 12/12/2022] Open
Abstract
Transplantation of allogeneic hematopoietic stem cells represents an established treatment for children with high-risk leukemia. However, steroid-refractory chronic graft-versus-host disease (SR-cGvHD) represents a severe life-threatening complication, for which there is no standard therapy. After failing several lines of immunosuppressive and biological treatment, we applied an immunoablative therapy with re-transplantation of purified CD34+ donor stem cells to reset the aberrant immune system. Two pediatric patients, who had been transplanted for high-risk acute lymphoblastic leukemia, underwent the procedure. Interestingly, enough stem cells could be mobilized, harvested, and purified to be used as grafts more than one year after allogeneic transplantation under intensive immunosuppressive therapy and ongoing SR-cGvHD. With a follow-up of 8 and 22 months, respectively, both patients are without immunosuppressive therapy and do not show signs of active disease. Regeneration of skin manifestations started promptly, other damaged organs did not progress and continue to show recovery from severe fibrotic transformation. Bone marrow function is robust and T cell receptor repertoires showed polyclonal immune reconstitution. In conclusion, stem cell harvest and re-transplantation of human CD34+-selected allogeneic stem cells is possible and represents a new therapeutic option in SR-cGvHD by resetting a profoundly disturbed immune network.
Collapse
|
|
16
|
Møller DL, Kielsen K, Nielsen CH, Sengeløv H, Pedersen AE, Ryder LP, Müller K. Thymic stromal lymphopoietin levels after allogeneic hematopoietic stem cell transplantation. Immunopharmacol Immunotoxicol 2022; 44:1004-1012. [PMID: 35899395 DOI: 10.1080/08923973.2022.2102989] [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] [Indexed: 12/13/2022]
Abstract
BACKGROUND Thymic stromal lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. METHODS We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry. RESULTS TSLP levels rose after initiation of the conditioning to peak at day +21 after HSCT (p = .03), where TSLP levels correlated with counts of neutrophils (rho = 0.36, p = .04), monocytes (rho = 0.58, p = .006), and lymphocytes (rho = 0.59, p = .02). Overall absolute TSLP levels were not associated with acute or chronic graft-vs-host disease (a/cGvHD). However, patients mounting a sustained increase in TSLP levels at day +90 had a higher risk of cGvHD compared to patients who had returned to pre-conditioning levels at that stage (cumulative incidence: 77% vs. 38%, p = .01). CONCLUSION In conclusion, this study suggests a role of TSLP in immune reconstitution and alloreactivity post-HSCT. lymphopoietin (TSLP) is an immunoregulatory, Th2-polarizing cytokine produced by epithelial cells. We hypothesized that TSLP affects immune reconstitution after hematopoietic stem cell transplantation (HSCT) leading to increased alloreactivity. We measured plasma TSLP by ELISA in 38 patients and assessed the immune reconstitution by flow cytometry.
Collapse
Affiliation(s)
- Dina Leth Møller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Katrine Kielsen
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Claus Henrik Nielsen
- Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Henrik Sengeløv
- Department of Hematology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | | | - Lars Peter Ryder
- The Tissue Typing Laboratory, Department of Clinical Immunology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark
| | - Klaus Müller
- Department of Pediatrics and Adolescent Medicine, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute for Inflammation Research, Department of Rheumatology and Spine Diseases, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark.,Institute of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark
| |
Collapse
|
|
17
|
Levien TL, Baker DE. Formulary Drug Review: Belumosudil. Hosp Pharm 2022; 57:435-441. [PMID: 35898245 PMCID: PMC9310299 DOI: 10.1177/00185787211061381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/03/2023]
Abstract
Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well-documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are available online to subscribers. Monographs can be customized to meet the needs of a facility. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, contact Wolters Kluwer customer service at 866-397-3433.
Collapse
|
|
18
|
Albrecht M, Halle O, Gaedcke S, Pallenberg ST, Camargo Neumann J, Witt M, Roediger J, Schumacher M, Jirmo AC, Warnecke G, Jonigk D, Braubach P, DeLuca D, Hansen G, Dittrich AM. Interleukin-17A and interleukin-22 production by conventional and non-conventional lymphocytes in three different end-stage lung diseases. Clin Transl Immunology 2022; 11:e1398. [PMID: 35757569 PMCID: PMC9202301 DOI: 10.1002/cti2.1398] [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: 10/22/2021] [Revised: 05/11/2022] [Accepted: 06/01/2022] [Indexed: 11/10/2022] Open
Abstract
Objectives The contribution of adaptive vs. innate lymphocytes to IL-17A and IL-22 secretion at the end stage of chronic lung diseases remains largely unexplored. In order to uncover tissue- and disease-specific secretion patterns, we compared production patterns of IL-17A and IL-22 in three different human end-stage lung disease entities. Methods Production of IL-17A, IL-22 and associated cytokines was assessed in supernatants of re-stimulated lymphocytes by multiplex assays and multicolour flow cytometry of conventional T cells, iNKT cells, γδ T cells and innate lymphoid cells in bronchial lymph node and lung tissue from patients with emphysema (n = 19), idiopathic pulmonary fibrosis (n = 14) and cystic fibrosis (n = 23), as well as lung donors (n = 17). Results We detected secretion of IL-17A and IL-22 by CD4+ T cells, CD8+ T cells, innate lymphoid cells, γδ T cells and iNKT cells in all end-stage lung disease entities. Our analyses revealed disease-specific contributions of individual lymphocyte subpopulations to cytokine secretion patterns. We furthermore found the high levels of microbial detection in CF samples to associate with a more pronounced IL-17A signature upon antigen-specific and unspecific re-stimulation compared to other disease entities and lung donors. Conclusion Our results show that both adaptive and innate lymphocyte populations contribute to IL-17A-dependent pathologies in different end-stage lung disease entities, where they establish an IL-17A-rich microenvironment. Microbial colonisation patterns and cytokine secretion upon microbial re-stimulation suggest that pathogens drive IL-17A secretion patterns in end-stage lung disease.
Collapse
Affiliation(s)
- Melanie Albrecht
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany.,Molecular Allergology Paul-Ehrlich-Institut, Federal Institute for Vaccines and Biomedicines Langen Germany.,Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| | - Olga Halle
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany.,Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| | - Svenja Gaedcke
- Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| | - Sophia T Pallenberg
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany
| | - Julia Camargo Neumann
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany
| | - Marius Witt
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany
| | - Johanna Roediger
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany
| | - Marina Schumacher
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany
| | - Adan Chari Jirmo
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany.,Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| | - Gregor Warnecke
- Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany.,Department of Cardiac Surgery Heidelberg Medical School Heidelberg Germany
| | - Danny Jonigk
- Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany.,Institute of Pathology Hannover Medical School Hannover Germany
| | - Peter Braubach
- Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany.,Institute of Pathology Hannover Medical School Hannover Germany
| | - David DeLuca
- Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| | - Gesine Hansen
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany.,Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| | - Anna-Maria Dittrich
- Pediatric Pneumology, Allergology and Neonatology Hannover Medical School Hannover Germany.,Biomedical Research in Endstage and Obstructive Lung Diseases (BREATH), German Center for Lung Research (DZL) Hannover Germany
| |
Collapse
|
|
19
|
Han S, Yang W, Qin C, Du Y, Ding M, Yin H, Xu T. Intratumoral fibrosis and patterns of immune infiltration in clear cell renal cell carcinoma. BMC Cancer 2022; 22:661. [PMID: 35710350 PMCID: PMC9205105 DOI: 10.1186/s12885-022-09765-0] [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: 11/12/2021] [Accepted: 06/07/2022] [Indexed: 11/23/2022] Open
Abstract
Background Intratumoral fibrosis was positively correlated with histological grade of renal clear cell carcinoma (ccRCC) and intratumoral inflammation. However, the association of intratumoral fibrosis with the immune infiltration of ccRCC was few evaluated. Methods We used the second harmonic generation (SHG)-based imaging technology and evaluated the intratumoral fibrosis in ccRCC, and then divided the patients into the high fibrosis group (HF) and the low fibrosis group (LF). Meanwhile, the Kaplan–Meier survival curve analysis was performed to analyze the relationship between intratumoral fibrosis and the disease-free survival rate. Antibody arrays were used for seeking difference in cytokines and immune infiltration between the HF group (N = 11) and LF group (N = 11). The selected immune infiltration marker was then verified by immunohistochemistry (IHC) staining in 45 ccRCC samples. Results Out of 640 cytokines and immune infiltration markers, we identified 115 proteins that were significantly different in quantity between ccRCC and adjacent normal tissues. In addition, the Venn diagram indicated that six proteins, including Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4), were significantly associated with intratumoral fibrosis (p < 0.05). The GO/KEGG enrichment analysis indicated that the proteins associated with intratumoral fibrosis were involved in the immunity and tumor-infiltrating lymphocytes. The expression of the CTLA4 was negatively correlated with collagen level, confirmed by IHC staining of CTLA4 (p < 0.05). Conclusions The study indicated that the intratumoral fibrosis level was negatively correlated with the expression of CTLA4 in the tumor immune microenvironment of the ccRCC, which posed the potential value of targeting the stroma of the tumor, a supplement to immunotherapy. However, the specific mechanism of this association is still unclear and needs further investigation. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-022-09765-0.
Collapse
Affiliation(s)
- Songchen Han
- Department of Urology, Peking University People's Hospital, No.11 South Xizhimen Street, Beijing, 100044, China
| | - Wenbo Yang
- Department of Urology, Peking University People's Hospital, No.11 South Xizhimen Street, Beijing, 100044, China
| | - Caipeng Qin
- Department of Urology, Peking University People's Hospital, No.11 South Xizhimen Street, Beijing, 100044, China
| | - Yiqing Du
- Department of Urology, Peking University People's Hospital, No.11 South Xizhimen Street, Beijing, 100044, China
| | - Mengting Ding
- Department of Urology, Peking University People's Hospital, No.11 South Xizhimen Street, Beijing, 100044, China
| | - Huaqi Yin
- Department of Urology, The Affiliated Cancer Hospital of Zhengzhou University & Henan Cancer Hospital, Zhengzhou, 450008, China.
| | - Tao Xu
- Department of Urology, Peking University People's Hospital, No.11 South Xizhimen Street, Beijing, 100044, China.
| |
Collapse
|
|
20
|
Pinto GR, Sarmento VA, de Carvalho-Filho PC, Fortuna VA, Costa RDS, Conceição RR, Trindade SC. Gene expression profile of chronic oral graft-versus-host disease. PLoS One 2022; 17:e0267325. [PMID: 35486633 PMCID: PMC9053775 DOI: 10.1371/journal.pone.0267325] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 04/06/2022] [Indexed: 11/23/2022] Open
Abstract
Among the complications observed after allogeneic hematopoietic stem cell transplantation, graft-versus-host disease (GVHD) is the primary cause of post-transplant mortality. The oral cavity is the second most affected organ target in chronic GVHD. Tissue damage results from the upregulation of inflammatory mediators, which play a critical role in the immunopathogenesis of the disease. This case series observational study aims to evaluate the participation of cytokines, chemokines, transcription factors, and heat shock proteins in the pathogenesis of oral GVHD (oGVHD), describing the mRNA expression of 28 genes selected. Peripheral blood mononuclear cells were isolated from six participants with oGVHD and two without GVHD, and relative expression of transcripts with established roles as inflammatory mediators was determined in triplicate using the human RT2 Profiler™ PCR Array. The gene expression levels in the group with oGVHD were mainly up-regulated compared to those without GVHD. PBMC from oGVDH expressed consistently higher IFN-γ, TNF, IL-1β, CCL2, HSP60 (HSPD1) and HSP90 (HSP90B1). These results can provide a basis for developing new molecular diagnostics and targets therapies for the clinical management of oGVHD.
Collapse
Affiliation(s)
- Giselle Rocha Pinto
- Department of Dentistry, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
- * E-mail:
| | | | | | - Vitor Antonio Fortuna
- Health Science Institute, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
| | - Ryan dos Santos Costa
- Health Science Institute, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
| | | | - Soraya Castro Trindade
- Health Science Institute, Federal University of Bahia (UFBA), Salvador, Bahia, Brazil
- Department of Dentistry, Feira de Santana State University (UEFS), Feira de Santana, Bahia, Brazil
| |
Collapse
|
|
21
|
Agbogan VA, Gastineau P, Tejerina E, Karray S, Zavala F. CpG-Activated Regulatory B-Cell Progenitors Alleviate Murine Graft-Versus-Host-Disease. Front Immunol 2022; 13:790564. [PMID: 35479094 PMCID: PMC9035844 DOI: 10.3389/fimmu.2022.790564] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2021] [Accepted: 03/21/2022] [Indexed: 11/13/2022] Open
Abstract
Development of Graft Versus Host Disease (GVHD) represents a major impediment in allogeneic hematopoietic stem cell transplantation (HSCT). The observation that the presence of bone marrow and circulating hematogones correlated with reduced GVHD risks prompted us to evaluate whether B-cell progenitors, which provide protection in various autoimmune disease models following activation with the TLR-9 agonist CpG (CpG-proBs), could likewise reduce this allogeneic disorder. In a murine model of GVHD that recapitulates an initial phase of acute GVHD followed by a phase of chronic sclerodermatous GVHD, we found that CpG-proBs, adoptively transferred during the initial phase of disease, reduced the diarrhea score and mostly prevented cutaneous fibrosis. Progenitors migrated to the draining lymph nodes and to the skin where they mainly differentiated into follicular B cells. CpG activation and IFN-γ expression were required for the protective effect, which resulted in reduced CD4+ T-cell-derived production of critical cytokines such as TGF-β, IL-13 and IL-21. Adoptive transfer of CpG-proBs increased the T follicular regulatory to T follicular helper (Tfr/Tfh) ratio. Moreover, CpG-proBs privileged the accumulation of IL-10-positive CD8+ T cells, B cells and dendritic cells in the skin. However, CpG-proBs did not improve survival. Altogether, our findings support the notion that adoptively transferred CpG-proBs exert immunomodulating effect that alleviates symptoms of GVHD but require additional anti-inflammatory strategy to improve survival.
Collapse
Affiliation(s)
- Viviane A. Agbogan
- Université Paris Cité, INSERM U1151, CNRS UMR8152, Institut Necker Enfants Malades (INEM), Paris, France
| | - Pauline Gastineau
- Université Paris Cité, INSERM U1151, CNRS UMR8152, Institut Necker Enfants Malades (INEM), Paris, France
| | - Emmanuel Tejerina
- Université Paris Cité, INSERM U1151, CNRS UMR8152, Institut Necker Enfants Malades (INEM), Paris, France
| | - Saoussen Karray
- Université Paris Cité, INSERM U976, Institut de Recherche Saint-Louis (IRSL), Hôpital Saint-Louis, Paris, France
| | - Flora Zavala
- Université Paris Cité, INSERM U1151, CNRS UMR8152, Institut Necker Enfants Malades (INEM), Paris, France
- *Correspondence: Flora Zavala, ; orcid.org/0000-0002-2338-6802
| |
Collapse
|
|
22
|
Biliary atresia: Graft-versus-host disease with maternal microchimerism as an etiopathogenesis. Transfus Apher Sci 2022; 61:103410. [DOI: 10.1016/j.transci.2022.103410] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
|
|
23
|
Sobkowiak-Sobierajska A, Lindemans C, Sykora T, Wachowiak J, Dalle JH, Bonig H, Gennery A, Lawitschka A. Management of Chronic Graft-vs.-Host Disease in Children and Adolescents With ALL: Present Status and Model for a Personalised Management Plan. Front Pediatr 2022; 10:808103. [PMID: 35252060 PMCID: PMC8894895 DOI: 10.3389/fped.2022.808103] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2021] [Accepted: 01/24/2022] [Indexed: 12/18/2022] Open
Abstract
Herein we review current practice regarding the management of chronic graft-vs.-host disease (cGvHD) in paediatric patients after allogeneic haematopoietic stem cell transplantation (HSCT) for acute lymphoblastic leukaemia (ALL). Topics covered include: (i) the epidemiology of cGvHD; (ii) an overview of advances in our understanding cGvHD pathogenesis; (iii) current knowledge regarding risk factors for cGvHD and prevention strategies complemented by biomarkers; (iii) the paediatric aspects of the 2014 National Institutes for Health-defined diagnosis and grading of cGvHD; and (iv) current options for cGvHD treatment. We cover topical therapy and newly approved tyrosine kinase inhibitors, emphasising the use of immunomodulatory approaches in the context of the delicate counterbalance between immunosuppression and immune reconstitution as well as risks of relapse and infectious complications. We examine real-world approaches of response assessment and tapering schedules of treatment. Furthermore, we report on the optimal timepoints for therapeutic interventions and changes in relation to immune reconstitution and risk of relapse/infection. Additionally, we review the different options for anti-infectious prophylaxis. Finally, we put forth a theory of a holistic view of paediatric cGvHD and its associated manifestations and propose a checklist for individualised risk evaluation with aggregated considerations including site-specific cGvHD evaluation with attention to each individual's GvHD history, previous medical history, comorbidities, and personal tolerance and psychosocial circumstances. To complement this checklist, we present a treatment algorithm using representative patients to inform the personalised management plans for patients with cGvHD after HSCT for ALL who are at high risk of relapse.
Collapse
Affiliation(s)
| | - Caroline Lindemans
- Department of Pediatrics, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Pediatric Blood and Bone Marrow Transplantation, Princess Máxima Center, Utrecht, Netherlands
| | - Tomas Sykora
- Department of Pediatric Hematology and Oncology - Haematopoietic Stem Cell Transplantation Unit, National Institute of Children's Diseases and Medical Faculty, Comenius University, Bratislava, Slovakia
| | - Jacek Wachowiak
- Department of Pediatric Oncology, Hematology and Transplantology, Poznan University of Medical Sciences, Poznan, Poland
| | - Jean-Hugues Dalle
- Hematology and Immunology Department, Robert-Debré Hospital, Assistance Publique-Hôpitaux de Paris and University of Paris, Paris, France
| | - Halvard Bonig
- Goethe University Medical Center, Institute of Transfusion Medicine and Immunohematology, and German Red Cross Blood Center Frankfurt, Frankfurt, Germany
| | - Andrew Gennery
- Medical School, Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Anita Lawitschka
- Stem Cell Transplantation Unit, St. Anna Children's Hospital, Medical University Vienna, Vienna, Austria.,St. Anna Children's Cancer Research Institute, Vienna, Austria
| |
Collapse
|
|
24
|
Muraji T, Masuya R, Harumatsu T, Kawano T, Muto M, Ieiri S. New insights in understanding biliary atresia from the perspectives on maternal microchimerism. Front Pediatr 2022; 10:1007987. [PMID: 36210938 PMCID: PMC9539747 DOI: 10.3389/fped.2022.1007987] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Accepted: 09/02/2022] [Indexed: 11/13/2022] Open
Abstract
Biliary atresia (BA) is a fibroinflammatory cholangiopathy and portal venopathy. It is of unknown etiology and is associated with systemic immune dysregulation, in which the first insult begins before birth. Maternal microchimerism is a naturally occurring phenomenon during fetal life in which maternal alloantigens promote the development of tolerogenic fetal regulatory T-cells in utero. However, maternal cells may alter the fetus's response to self-antigens and trigger an autoimmune response under certain histocompatibility combinations between the mother and the fetus. A recent report on a set of dizygotic discordant twins with BA, one of whose placentae showed villitis of unknown etiology, implies a certain immune-mediated conflict between the fetus with BA and the mother. Maternal chimeric cells persist postnatally for various time spans and can cause cholangitis, which ultimately leads to liver failure. In contrast, patients who eliminate maternal chimeric cells may retain their liver function.
Collapse
Affiliation(s)
- Toshihiro Muraji
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Ryuta Masuya
- Division of the Gastrointestinal, Endocrine and Pediatric Surgery, Department of Surgery, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan
| | - Toshio Harumatsu
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Takafumi Kawano
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Mitsuru Muto
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| | - Satoshi Ieiri
- Department of Pediatric Surgery, Research Field in Medicine and Health Sciences, Medical and Dental Sciences Area, Research and Education Assembly, Kagoshima University, Kagoshima, Japan
| |
Collapse
|
|
25
|
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.
Collapse
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
| |
Collapse
|
|
26
|
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: 88] [Impact Index Per Article: 22.0] [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.
Collapse
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
| |
Collapse
|
|
27
|
Jeljeli M, Chêne C, Chouzenoux S, Thomas M, Segain B, Doridot L, Nicco C, Batteux F. LPS low-Macrophages Alleviate the Outcome of Graft- Versus-Host Disease Without Aggravating Lymphoma Growth in Mice. Front Immunol 2021; 12:670776. [PMID: 34413847 PMCID: PMC8369416 DOI: 10.3389/fimmu.2021.670776] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2021] [Accepted: 07/07/2021] [Indexed: 02/06/2023] Open
Abstract
Despite significant therapeutic advances, graft-versus-host disease (GvHD) remains the main life-threatening complication following allogeneic hematopoietic stem cell transplantation. The pathogenesis of GvHD is dominated by a dysregulated allogeneic immune response that drives fibrosis and autoimmunity in chronic forms. A multitude of cell therapy approaches, including infusion of myeloid cells, has been proposed to prevent GvHD through tolerance induction but yielded variable results. Myeloid cells like macrophages can be reprogrammed to develop adaptive-like features following antigenic challenge to reinforce or inhibit a subsequent immune response; a phenomenon termed ‘trained immunity’. Here we report that, whereas LPSlow-trained macrophages elicit a suppressor effect on allogeneic T cell proliferation and function in vitro in an IL-10-dependent manner, Bacille Calmette et Guérin (BCG)-trained macrophages exert an opposite effect. In a murine model of sclerodermatous chronic GvHD, LPSlow-trained macrophages attenuate clinical signs of GvHD with significant effects on T cell phenotype and function, autoantibodies production, and tissue fibrosis. Furthermore, infusion of LPSlow-macrophages significantly improves survival in mice with acute GvHD. Importantly, we also provide evidence that LPSlow-macrophages do not accelerate A20-lymphoma tumor growth, which is significantly reduced upon transfer of BCG-macrophages. Collectively, these data indicate that macrophages can be trained to significantly inhibit in vitro and in vivo allo-reactive T cell proliferation without exhibiting pro-tumoral effect, thereby opening the way to promising clinical applications.
Collapse
Affiliation(s)
- Mohamed Jeljeli
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France.,Université de Paris, Faculté de Médecine, AP-HP-Centre Université de Paris, Hôpital Cochin, Service d'immunologie biologique, Paris, France
| | - Charlotte Chêne
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Sandrine Chouzenoux
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Marine Thomas
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Benjamin Segain
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Ludivine Doridot
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Carole Nicco
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France
| | - Frédéric Batteux
- Département 3I «Infection, Immunité et Inflammation», Institut Cochin, INSERM U1016, Université de Paris, Paris, France.,Université de Paris, Faculté de Médecine, AP-HP-Centre Université de Paris, Hôpital Cochin, Service d'immunologie biologique, Paris, France
| |
Collapse
|
|
28
|
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: 24] [Impact Index Per Article: 6.0] [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.
Collapse
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
| |
Collapse
|
|
29
|
Wheeler DS, Misumi K, Walker NM, Vittal R, Combs MP, Aoki Y, Braeuer RR, Lama VN. Interleukin 6 trans-signaling is a critical driver of lung allograft fibrosis. Am J Transplant 2021; 21:2360-2371. [PMID: 33249747 PMCID: PMC8809084 DOI: 10.1111/ajt.16417] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 11/06/2020] [Accepted: 11/23/2020] [Indexed: 01/25/2023]
Abstract
Histopathologic examination of lungs afflicted by chronic lung allograft dysfunction (CLAD) consistently shows both mononuclear cell (MNC) inflammation and mesenchymal cell (MC) fibroproliferation. We hypothesize that interleukin 6 (IL-6) trans-signaling may be a critical mediator of MNC-MC crosstalk and necessary for the pathogenesis of CLAD. Bronchoalveolar lavage (BAL) fluid obtained after the diagnosis of CLAD has approximately twofold higher IL-6 and soluble IL-6 receptor (sIL-6R) levels compared to matched pre-CLAD samples. Human BAL-derived MCs do not respond to treatment with IL-6 alone but have rapid and prolonged JAK2-mediated STAT3 Tyr705 phosphorylation when exposed to the combination of IL-6 and sIL-6R. STAT3 phosphorylation within MCs upregulates numerous genes causing increased invasion and fibrotic differentiation. MNC, a key source of both IL-6 and sIL-6R, produce minimal amounts of these proteins at baseline but significantly upregulate production when cocultured with MCs. Finally, the use of an IL-6 deficient recipient in a murine orthotopic transplant model of CLAD reduces allograft fibrosis by over 50%. Taken together these results support a mechanism where infiltrating MNCs are stimulated by resident MCs to release large quantities of IL-6 and sIL-6R which then feedback onto the MCs to increase invasion and fibrotic differentiation.
Collapse
Affiliation(s)
- David S Wheeler
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Keizo Misumi
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Natalie M Walker
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Ragini Vittal
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Michael P Combs
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Yoshiro Aoki
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Russell R Braeuer
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| | - Vibha N Lama
- Department of Internal Medicine, Division of Pulmonary and Critical Care Medicine, University of Michigan, Ann Arbor, Michigan, USA
| |
Collapse
|
|
30
|
Li H, Tsokos MG, Bhargava R, Adamopoulos IE, Menn-Josephy H, Stillman IE, Rosenstiel P, Jordan J, Tsokos GC. IL-23 reshapes kidney resident cell metabolism and promotes local kidney inflammation. J Clin Invest 2021; 131:142428. [PMID: 33956666 DOI: 10.1172/jci142428] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Accepted: 05/05/2021] [Indexed: 12/26/2022] Open
Abstract
Interstitial kidney inflammation is present in various nephritides in which serum interleukin 23 (IL-23) is elevated. Here we showed that murine and human renal tubular epithelial cells (TECs) expressing the IL-23 receptor (IL-23R) responded to IL-23 by inducing intracellular calcium flux, enhancing glycolysis, and upregulating calcium/calmodulin kinase IV (CaMK4), which resulted in suppression of the expression of the arginine-degrading enzyme arginase 1 (ARG1), thus increasing in situ levels of free L-arginine. Limited availability of arginine suppressed the ability of infiltrating T cells to proliferate and produce inflammatory cytokines. TECs from humans and mice with nephritis expressed increased levels of IL-23R and CaMK4 but reduced levels of ARG1. TEC-specific deletion of Il23r or Camk4 suppressed inflammation, whereas deletion of Arg1 exacerbated inflammation in different murine disease models. Finally, TEC-specific delivery of a CaMK4 inhibitor specifically curbed renal inflammation in lupus-prone mice without affecting systemic inflammation. Our data offer the first evidence to our knowledge of the immunosuppressive capacity of TECs through a mechanism that involves competitive uptake of arginine and signify the importance of modulation of an inflammatory cytokine in the function of nonlymphoid cells, which leads to the establishment of an inflammatory microenvironment. New approaches to treat kidney inflammation should consider restoring the immunosuppressive capacity of TECs.
Collapse
Affiliation(s)
- Hao Li
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Maria G Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Rhea Bhargava
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Iannis E Adamopoulos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Hanni Menn-Josephy
- Department of Medicine, Renal Section, Boston University School of Medicine, Boston, Massachusetts, USA
| | - Isaac E Stillman
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology, Kiel University and University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Jarrat Jordan
- Janssen Research & Development, LLC, Spring House, Pennsylvania, USA
| | - George C Tsokos
- Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| |
Collapse
|
|
31
|
Socié G, Kean LS, Zeiser R, Blazar BR. Insights from integrating clinical and preclinical studies advance understanding of graft-versus-host disease. J Clin Invest 2021; 131:149296. [PMID: 34101618 PMCID: PMC8203454 DOI: 10.1172/jci149296] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
As a result of impressive increases in our knowledge of rodent and human immunology, the understanding of the pathophysiologic mechanisms underlying graft-versus-host disease (GVHD) has dramatically improved in the past 15 years. Despite improved knowledge, translation to clinical care has not proceeded rapidly, and results from experimental models have been inconsistent in their ability to predict the clinical utility of new therapeutic agents. In parallel, new tools in immunology have allowed in-depth analyses of the human system and have recently been applied in the field of clinical GVHD. Notwithstanding these advances, there is a relative paucity of mechanistic insights into human translational research, and this remains an area of high unmet need. Here we review selected recent advances in both preclinical experimental transplantation and translational human studies, including new insights into human immunology, the microbiome, and regenerative medicine. We focus on the fact that both approaches can interactively improve our understanding of both acute and chronic GVHD biology and open the door to improved therapeutics and successes.
Collapse
Affiliation(s)
- Gérard Socié
- Hematology-Transplantation, Assistance Publique–Hôpitaux de Paris (APHP), Hospital Saint Louis, Paris, France
- INSERM UMR 976 (Team Insights) and University of Paris, Paris, France
| | - Leslie S. Kean
- Division of Pediatric Hematology/Oncology, Boston Children’s Hospital, Boston, Massachusetts, USA
- Dana-Farber Cancer Institute, Boston, Massachusetts, USA
| | - Robert Zeiser
- Department of Medicine I, Faculty of Medicine, Medical Center–University of Freiburg, Freiburg, Germany
| | - Bruce R. Blazar
- Masonic Cancer Center and Department of Pediatrics, Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota, USA
| |
Collapse
|
|
32
|
Burns SS, Kapur R. Clonal Hematopoiesis of Indeterminate Potential as a Novel Risk Factor for Donor-Derived Leukemia. Stem Cell Reports 2021; 15:279-291. [PMID: 32783925 PMCID: PMC7419737 DOI: 10.1016/j.stemcr.2020.07.008] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Revised: 07/07/2020] [Accepted: 07/09/2020] [Indexed: 12/22/2022] Open
Abstract
Hematopoietic stem cell transplantation (HSCT) is a critical treatment modality for many hematological and non-hematological diseases that is being extended to treat older individuals. However, recent studies show that clonal hematopoiesis of indeterminate potential (CHIP), a common, asymptomatic condition characterized by the expansion of age-acquired somatic mutations in blood cell lineages, may be a risk factor for the development of donor-derived leukemia (DDL), unexplained cytopenias, and chronic graft-versus-host disease. CHIP may contribute to the pathogenesis of these significant transplant complications via various cell-autonomous and non-cell-autonomous mechanisms, and the clinical presentation of DDL may be broader than anticipated. A more comprehensive understanding of the contributions of CHIP to DDL may have important implications for the screening of donors and will improve the safety of HSCT. The objective of this review is to discuss studies linking DDL and CHIP and to explore potential mechanisms by which CHIP may contribute to DDL.
Collapse
Affiliation(s)
- Sarah S Burns
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA
| | - Reuben Kapur
- Department of Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Pediatrics, Herman B Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Molecular Biology and Biochemistry, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
| |
Collapse
|
|
33
|
Nair S, Vanathi M, Mukhija R, Tandon R, Jain S, Ogawa Y. Update on ocular graft-versus-host disease. Indian J Ophthalmol 2021; 69:1038-1050. [PMID: 33913829 PMCID: PMC8186644 DOI: 10.4103/ijo.ijo_2016_20] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Ocular graft-versus-host disease (oGVHD) occurs as a complication following hematopoietic stem cell transplantation and is associated with significant ocular morbidity resulting in a marked reduction in the quality of life. With no current consensus on treatment protocols, management becomes challenging as recurrent oGVHD often refractory to conventional treatment. Most authors now diagnose and grade the disease based on criteria provided by the National Institutes of Health Consensus Conference (NIH CC) or the International Chronic oGVHD (ICCGVHD) consensus group. This article will provide an insight into the diagnostic criteria of oGVHD, its classification, and clinical severity grading scales. The inflammatory process in oGVHD can involve the entire ocular surface including the eyelids, meibomian gland, corneal, conjunctiva, and lacrimal system. The varied clinical presentations and treatment strategies employed to manage them have been discussed in the present study. The recent advances in ocular surface imaging in oGVHD patients such as the use of meibography and in vivo confocal microscopy may help in early diagnosis and prognostication of the disease. Researching tear proteomics and identification of novel potential tear biomarkers in oGVHD patients is an exciting field as they may help in objectively diagnosing the disease and monitoring the response to treatment.
Collapse
Affiliation(s)
- Sridevi Nair
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Murugesan Vanathi
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Ritika Mukhija
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Radhika Tandon
- Cornea, Cataract & Refractive Surgery Services, Dr R P Centre, All India Institute of Medical Sciences, New Delhi, India
| | - Sandeep Jain
- Department of Ophthalmology, University of Chicago, USA
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
34
|
El Jurdi N, Elhusseini H, Beckman J, DeFor TE, Okoev G, Rogosheske J, Lazaryan A, Weiler K, Bachanova V, Betts BC, Blazar BR, Brunstein CG, He F, Holtan SG, Janakiram M, Gangaraju R, Maakaron J, MacMillan ML, Rashidi A, Warlick ED, Bhatia S, Vercellotti G, Weisdorf DJ, Arora M. High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group. Blood Cancer J 2021; 11:96. [PMID: 34006823 PMCID: PMC8131386 DOI: 10.1038/s41408-021-00488-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/20/2021] [Accepted: 04/29/2021] [Indexed: 02/08/2023] Open
Abstract
Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15–29%) with a median time from cGVHD to TEE of 234 days (range, 12–2050). Median time to the development of LE DVT or PE was 107 (range, 12–1925) compared to 450 days (range, 158–1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0–20%), 17% (95% CI, 9–25%), and 38% (95% CI, 22–55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1–22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0–7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1–5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.
Patients with chronic GVHD after allogeneic hematopoietic cell transplantation are at high risk for thromboembolic events occurring years after diagnosis. More severe chronic GVHD, non-O donor-recipient ABO compared to O-O match and personal history of coronary artery disease are associated with higher risk of thromboembolic events.
Collapse
Affiliation(s)
- Najla El Jurdi
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.
| | - Heba Elhusseini
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Joan Beckman
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Todd E DeFor
- Biostatistics and Informatics, Clinical and Translational Science Institute, University of Minnesota, Minneapolis, MN, USA
| | - Grigori Okoev
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - John Rogosheske
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Aleksandr Lazaryan
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Kristen Weiler
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Veronika Bachanova
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Brian C Betts
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Bruce R Blazar
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Claudio G Brunstein
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Fiona He
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Shernan G Holtan
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Murali Janakiram
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Radhika Gangaraju
- Department of Pediatrics, University of Alabama, Tuscaloosa, AL, USA
| | - Joseph Maakaron
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Margaret L MacMillan
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Armin Rashidi
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Erica D Warlick
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Smita Bhatia
- Department of Pediatrics, University of Alabama, Tuscaloosa, AL, USA
| | - Gregory Vercellotti
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Daniel J Weisdorf
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| | - Mukta Arora
- Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA
| |
Collapse
|
|
35
|
Hill GR, Betts BC, Tkachev V, Kean LS, Blazar BR. Current Concepts and Advances in Graft-Versus-Host Disease Immunology. Annu Rev Immunol 2021; 39:19-49. [PMID: 33428454 PMCID: PMC8085043 DOI: 10.1146/annurev-immunol-102119-073227] [Citation(s) in RCA: 107] [Impact Index Per Article: 26.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Worldwide, each year over 30,000 patients undergo an allogeneic hema-topoietic stem cell transplantation with the intent to cure high-risk hematologic malignancy, immunodeficiency, metabolic disease, or a life-threatening bone marrow failure syndrome. Despite substantial advances in donor selection and conditioning regimens and greater availability of allograft sources, transplant recipients still endure the morbidity and mortality of graft-versus-host disease (GVHD). Herein, we identify key aspects of acute and chronic GVHD pathophysiology, including host/donor cell effectors, gut dysbiosis, immune system and cytokine imbalance, and the interface between inflammation and tissue fibrosis. In particular, we also summarize the translational application of this heightened understanding of immune dysregulation in the design of novel therapies to prevent and treat GVHD.
Collapse
Affiliation(s)
- Geoffrey R Hill
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA;
- Division of Medical Oncology University of Washington, Seattle, Washington 98109, USA
| | - Brian C Betts
- Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota 55455, USA
| | - Victor Tkachev
- Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; ,
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Leslie S Kean
- Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, MA 02115, USA; ,
- Department of Medical Oncology, Dana Farber Cancer Institute, Boston, MA 02215, USA
- Department of Pediatrics, Harvard Medical School, Boston, Massachusetts 02115, USA
| | - Bruce R Blazar
- Division of Blood and Marrow Transplantation, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota 55455, USA;
| |
Collapse
|
|
36
|
Kitko CL, Pidala J, Schoemans HM, Lawitschka A, Flowers ME, Cowen EW, Tkaczyk E, Farhadfar N, Jain S, Steven P, Luo ZK, Ogawa Y, Stern M, Yanik GA, Cuvelier GDE, Cheng GS, Holtan SG, Schultz KR, Martin PJ, Lee SJ, Pavletic SZ, Wolff D, Paczesny S, Blazar BR, Sarantopoulos S, Socie G, Greinix H, Cutler C. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: IIa. The 2020 Clinical Implementation and Early Diagnosis Working Group Report. Transplant Cell Ther 2021; 27:545-557. [PMID: 33839317 PMCID: PMC8803210 DOI: 10.1016/j.jtct.2021.03.033] [Citation(s) in RCA: 104] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Accepted: 03/31/2021] [Indexed: 12/11/2022]
Abstract
Recognition of the earliest signs and symptoms of chronic graft-versus-host disease (GVHD) that lead to severe manifestations remains a challenge. The standardization provided by the National Institutes of Health (NIH) 2005 and 2014 consensus projects has helped improve diagnostic accuracy and severity scoring for clinical trials, but utilization of these tools in routine clinical practice is variable. Additionally, when patients meet the NIH diagnostic criteria, many already have significant morbidity and possibly irreversible organ damage. The goals of this early diagnosis project are 2-fold. First, we provide consensus recommendations regarding implementation of the current NIH diagnostic guidelines into routine transplant care, outside of clinical trials, aiming to enhance early clinical recognition of chronic GVHD. Second, we propose directions for future research efforts to enable discovery of new, early laboratory as well as clinical indicators of chronic GVHD, both globally and for highly morbid organ-specific manifestations. Identification of early features of chronic GVHD that have high positive predictive value for progression to more severe manifestations of the disease could potentially allow for future pre-emptive clinical trials.
Collapse
Affiliation(s)
- Carrie L Kitko
- Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee.
| | - Joseph Pidala
- Blood and Marrow Transplantation and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
| | - Hélène M Schoemans
- Department of Hematology, University Hospitals Leuven and KU Leuven, Leuven, Belgium
| | - Anita Lawitschka
- St. Anna Children's Hospital, Children's Cancer Research Institute, Vienna, Austria
| | - Mary E Flowers
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Edward W Cowen
- Dermatology Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, Bethesda, Maryland
| | - Eric Tkaczyk
- Research & Dermatology Services, Department of Veterans Affairs, Nashville, Tennessee; Vanderbilt Dermatology Translational Research Clinic, Department of Dermatology, Vanderbilt University Medical Center, Nashville, Tennessee; Vanderbilt-Ingram Cancer Center, Nashville, Tennessee
| | - Nosha Farhadfar
- Division of Hematology/Oncology, University of Florida College of Medicine, Gainesville, Florida
| | - Sandeep Jain
- Department of Ophthalmology, University of Illinois at Chicago, Chicago, Illinois
| | - Philipp Steven
- Division for Dry-Eye Disease and Ocular GVHD, Department of Ophthalmology, Medical Faculty and University Hospital, University of Cologne, Cologne, Germany
| | - Zhonghui K Luo
- Department of Ophthalmology, Massachusetts Eye and Ear, Harvard University, Boston, Massachusetts
| | - Yoko Ogawa
- Department of Ophthalmology, Keio University School of Medicine, Tokyo, Japan
| | - Michael Stern
- Department of Ophthalmology, University of Illinois at Chicago, Chicago, Illinois; ImmunEyez LLC, Irvine, California
| | - Greg A Yanik
- Department of Pediatrics, University of Michigan, Ann Arbor, Michigan
| | - Geoffrey D E Cuvelier
- Pediatric Blood and Marrow Transplantation, Department of Pediatric Oncology-Hematology-BMT, CancerCare Manitoba, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Guang-Shing Cheng
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Shernan G Holtan
- Division of Hematology, Oncology, and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, Minnesota
| | - Kirk R Schultz
- Pediatric Hematology/Oncology/BMT, BC Children's Hospital, Vancouver, British Columbia, Canada
| | - Paul J Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Stephanie J Lee
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Steven Z Pavletic
- Center for Cancer Research, National Cancer Institute, Bethesda, Maryland
| | - Daniel Wolff
- Department of Internal Medicine III, University Hospital of Regensburg, Regensburg, Germany
| | - Sophie Paczesny
- Department of Microbiology and Immunology, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina
| | - Bruce R Blazar
- Department of Pediatrics, Division of Blood & Marrow Transplantation & Cellular Therapy, University of Minnesota, Minneapolis, Minnesota
| | - Stephanie 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, INSERM U976, Paris, France
| | - Hildegard Greinix
- Clinical Division of Hematology, Medical University of Graz, Graz, Austria
| | - Corey Cutler
- Division of Stem Cell Transplantation and Cellular Therapy, Dana-Farber Cancer Institute, Boston, Massachusetts
| |
Collapse
|
|
37
|
Williams KM, Inamoto Y, Im A, Hamilton B, Koreth J, Arora M, Pusic I, Mays JW, Carpenter PA, Luznik L, Reddy P, Ritz J, Greinix H, Paczesny S, Blazar BR, Pidala J, Cutler C, Wolff D, Schultz KR, Pavletic SZ, Lee SJ, Martin PJ, Socie G, Sarantopoulos S. National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: I. The 2020 Etiology and Prevention Working Group Report. Transplant Cell Ther 2021; 27:452-466. [PMID: 33877965 DOI: 10.1016/j.jtct.2021.02.035] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023]
Abstract
Preventing chronic graft-versus-host disease (GVHD) remains challenging because the unique cellular and molecular pathways that incite chronic GVHD are poorly understood. One major point of intervention for potential prevention of chronic GVHD occurs at the time of transplantation when acute donor anti-recipient immune responses first set the events in motion that result in chronic GVHD. After transplantation, additional insults causing tissue injury can incite aberrant immune responses and loss of tolerance, further contributing to chronic GVHD. Points of intervention are actively being identified so that chronic GVHD initiation pathways can be targeted without affecting immune function. The major objective in the field is to continue basic studies and to translate what is learned about etiopathology to develop targeted prevention strategies that decrease the risk of morbid chronic GVHD without increasing the risks of cancer relapse or infection. Development of strategies to predict the risk of developing debilitating or deadly chronic GVHD is a high research priority. This working group recommends further interrogation into the mechanisms underpinning chronic GVHD development, and we highlight considerations for future trial design in prevention trials.
Collapse
Affiliation(s)
- Kirsten M Williams
- Division of Blood and Marrow Transplantation, Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Emory University, Atlanta, Georgia
| | - Yoshihiro Inamoto
- Department of Hematopoietic Stem Cell Transplantation, National Cancer Center Hospital, Tokyo, Japan
| | - Annie Im
- Division of Hematology Oncology, University of Pittsburgh, UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania
| | - Betty Hamilton
- Blood and Marrow Transplant Program, Department of Hematology and Medical Oncology, Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio
| | - John Koreth
- Dana-Farber Cancer Institute, Division of Hematologic Malignancies, Harvard Medical School, Boston, Massachusetts
| | - Mukta Arora
- Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, Minnesota
| | - Iskra Pusic
- BMT and Leukemia Section, Division of Oncology, Washington University School of Medicine, St. Louis, Missouri
| | - Jacqueline W Mays
- National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, Maryland
| | - Paul A Carpenter
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - Leo Luznik
- Division of Hematologic Malignancies, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Pavan Reddy
- Divsion of Hematology and Oncology, University of Michigan Rogel Cancer Center, Ann Arbor, Michigan
| | - Jerome Ritz
- Dana-Farber Cancer Institute, Division of Hematologic Malignancies, Harvard Medical School, Boston, Massachusetts
| | - Hildegard Greinix
- Clinical Division of Hematology, Medical University of Graz, Graz, Austria
| | - Sophie Paczesny
- Department of Microbiology and Immunology and Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina
| | - Bruce R Blazar
- Division of Pediatric Blood and Marrow Transplantation & Cellular Therapy, Department of Pediatrics, University of Minnesota, Minneapolis, Minnesota
| | - Joseph Pidala
- Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida
| | - Corey Cutler
- Dana-Farber Cancer Institute, Division of Hematologic Malignancies, Harvard Medical School, Boston, Massachusetts
| | - Daniel Wolff
- Department of Internal Medicine III, University Hospital of Regensburg, Regensburg, Germany
| | - Kirk R Schultz
- Pediatric Oncology, Hematology, and Bone Marrow Transplant, 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
| | - Paul J Martin
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington; Department of Medicine, University of Washington, Seattle, Washington
| | - Gerard Socie
- Hematology Transplantation, Saint Louis Hospital, AP-HP, and University of Paris, INSERM U976, Paris, France.
| | - Stefanie Sarantopoulos
- Division of Hematological Malignancies and Cellular Therapy, Department of Medicine, Duke Cancer Institute, Durham, North Carolina.
| |
Collapse
|
|
38
|
Hong C, Jin R, Dai X, Gao X. Functional Contributions of Antigen Presenting Cells in Chronic Graft-Versus-Host Disease. Front Immunol 2021; 12:614183. [PMID: 33717098 PMCID: PMC7943746 DOI: 10.3389/fimmu.2021.614183] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Accepted: 01/11/2021] [Indexed: 12/27/2022] Open
Abstract
Chronic graft-versus-host disease (cGVHD) is one of the most common reasons of late non-relapse morbidity and mortality of patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). While acute GVHD is considered driven by a pathogenic T cell dominant mechanism, the pathogenesis of cGVHD is much complicated and involves participation of a variety of immune cells other than pathogenic T cells. Existing studies have revealed that antigen presenting cells (APCs) play crucial roles in the pathophysiology of cGVHD. APCs could not only present auto- and alloantigens to prime and activate pathogenic T cells, but also directly mediate the pathogenesis of cGVHD via multiple mechanisms including infiltration into tissues/organs, production of inflammatory cytokines as well as auto- and alloantibodies. The studies of this field have led to several therapies targeting different APCs with promising results. This review will focus on the important roles of APCs and their contributions in the pathophysiology of cGVHD after allo-HSCT.
Collapse
Affiliation(s)
- Chao Hong
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Rong Jin
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Xiaoqiu Dai
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| | - Xiaoming Gao
- Institutes of Biology and Medical Sciences, Soochow University, Suzhou, China
| |
Collapse
|
|
39
|
Klouda T, Yuan K. Inflammation in Pulmonary Arterial Hypertension. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 1303:351-372. [PMID: 33788202 DOI: 10.1007/978-3-030-63046-1_19] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
Pulmonary artery hypertension (PAH) is a devastating cardiopulmonary disease characterized by vascular remodeling and obliteration of the precapillary pulmonary arterioles. Alterations in the structure and function of pulmonary vessels result in the resistance of blood flow and can progress to right-sided heart failure, causing significant morbidity and mortality. There are several types of PAH, and the disease can be familial or secondary to an underlying medical condition such as a connective tissue disorder or infection. Regardless of the cause, the exact pathophysiology and cellular interactions responsible for disease development and progression are largely unknown.There is significant evidence to suggest altered immune and vascular cells directly participate in disease progression. Inflammation has long been hypothesized to play a vital role in the development of PAH, as an altered or skewed immune response favoring a proinflammatory environment that can lead to the infiltration of cells such as lymphocytes, macrophages, and neutrophils. Current treatment strategies focus on the dilation of partially occluded vessels; however, such techniques have not resulted in an effective strategy to reverse or prevent vascular remodeling. Therefore, current studies in human and animal models have attempted to understand the underlying pathophysiology of pulmonary hypertension (PH), specifically focusing on the inflammatory cascade predisposing patients to disease so that better therapeutic targets can be developed to potentially reverse or prevent disease progression.The purpose of this chapter is to provide a comprehensive review of the expanding literature on the inflammatory process that participates in PH development while highlighting important and current studies in both animal and human models. While our primary focus will be on cells found in the adaptive and innate immune system, we will review all potential causes of PAH, including cells of the endothelium, pulmonary lymphatics, and genetic mutations predisposing patients. In addition, we will discuss current therapeutic options while highlighting potential future treatments and the questions that still remain unanswered.
Collapse
Affiliation(s)
- Timothy Klouda
- Divisions of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA
| | - Ke Yuan
- Divisions of Pulmonary Medicine, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
| |
Collapse
|
|
40
|
Wolff D, Fatobene G, Rocha V, Kröger N, Flowers ME. Steroid-refractory chronic graft-versus-host disease: treatment options and patient management. Bone Marrow Transplant 2021; 56:2079-2087. [PMID: 34218265 PMCID: PMC8410585 DOI: 10.1038/s41409-021-01389-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/14/2021] [Accepted: 06/22/2021] [Indexed: 02/05/2023]
Abstract
Chronic graft-versus-host disease (cGVHD) is one of the major causes of late mortality after allogenic hematopoietic stem cell transplantation. Moderate-to-severe cGVHD is associated with poor health-related quality of life and substantial disease burden. While corticosteroids with or without calcineurin inhibitors comprise the first-line treatment option, the prognosis for patients with steroid-refractory cGVHD (SR-cGVHD) remains poor. The mechanisms underlying steroid resistance are unclear, and there are no standard second-line treatment guidelines for patients with SR-cGVHD. In this review, we provide an overview on current treatment options of cGVHD and use a series of theoretical case studies to elucidate the rationale of choices of second- and third-line treatment options for patients with SR-cGVHD based on individual patient profiles.
Collapse
Affiliation(s)
- Daniel Wolff
- grid.411941.80000 0000 9194 7179Department of Internal Medicine III, University Hospital Regensburg, Regensburg, Germany
| | - Giancarlo Fatobene
- grid.411074.70000 0001 2297 2036Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil ,Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
| | - Vanderson Rocha
- grid.411074.70000 0001 2297 2036Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (HC-FMUSP), São Paulo, Brazil ,Vila Nova Star Hospital and IDOR, Rede D’Or, São Paulo, Brazil
| | - Nicolaus Kröger
- grid.13648.380000 0001 2180 3484Department of Stem Cell Transplantation, University Medical Center Hamburg, Hamburg, Germany
| | - Mary E. Flowers
- grid.34477.330000000122986657Clinical Research Division, Fred Hutchinson Cancer Research Center and Department of Medicine, University of Washington, Seattle, Seattle, WA USA
| |
Collapse
|
|
41
|
Giaccone L, Faraci DG, Butera S, Lia G, Di Vito C, Gabrielli G, Cerrano M, Mariotti J, Dellacasa C, Felicetti F, Brignardello E, Mavilio D, Bruno B. Biomarkers for acute and chronic graft versus host disease: state of the art. Expert Rev Hematol 2020; 14:79-96. [PMID: 33297779 DOI: 10.1080/17474086.2021.1860001] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
INTRODUCTION Despite significant advances in treatment and prevention, graft-versus-host disease (GVHD) still represents the main cause of morbidity and mortality after allogeneic hematopoietic stem cell transplantation. Thus, considerable research efforts have been made to find and validate reliable biomarkers for diagnosis, prognosis, and risk stratification of GVHD. AREAS COVERED In this review the most recent evidences on different types of biomarkers studied for GVHD, such as genetic, plasmatic, cellular markers, and those associated with microbiome, were summarized. A comprehensive search of peer-review literature was performed in PubMed including meta-analysis, preclinical and clinical trials, using the terms: cellular and plasma biomarkers, graft-versus-host disease, cytokines, and allogeneic hematopoietic stem cell transplantation. EXPERT OPINION In the near future, several validated biomarkers will be available to help clinicians in the diagnosis of GVHD, the identification of patients at high risk of GVHD development and in patients' stratification according to its severity. Then, immunosuppressive treatment could be tailored to each patient's real needs. However, more efforts are needed to achieve this goal. Although most of the proposed biomarkers currently lack validation with large-scale clinical data, their study led to improved knowledge of the biological basis of GVHD, and ultimately to implementation of GHVD treatment.
Collapse
Affiliation(s)
- Luisa Giaccone
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| | - Danilo Giuseppe Faraci
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| | - Sara Butera
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| | - Giuseppe Lia
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| | - Clara Di Vito
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center , Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine (Biometra), University of Milan , Milan, Italy
| | - Giulia Gabrielli
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| | - Marco Cerrano
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| | - Jacopo Mariotti
- Bone Marrow Transplant Unit, Humanitas Clinical and Research Center, IRCCS , Rozzano, Italy
| | - Chiara Dellacasa
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy
| | - Francesco Felicetti
- Transition Unit for Childhood Cancer Survivors, A.O.U. Città Della Salute E Della Scienza Di Torino , University of Torino , Torino, Italy
| | - Enrico Brignardello
- Transition Unit for Childhood Cancer Survivors, A.O.U. Città Della Salute E Della Scienza Di Torino , University of Torino , Torino, Italy
| | - Domenico Mavilio
- Unit of Clinical and Experimental Immunology, Humanitas Clinical and Research Center , Milan, Italy.,Department of Medical Biotechnologies and Translational Medicine (Biometra), University of Milan , Milan, Italy
| | - Benedetto Bruno
- Department of Oncology/Hematology, Stem Cell Transplant Program, A.O.U. Città Della Salute E Della Scienza Di Torino, Presidio Molinette , Torino, Italy.,Department of Molecular Biotechnology and Health Sciences, University of Torino , Torino, Italy
| |
Collapse
|
|
42
|
Introna M, Golay J. Tolerance to Bone Marrow Transplantation: Do Mesenchymal Stromal Cells Still Have a Future for Acute or Chronic GvHD? Front Immunol 2020; 11:609063. [PMID: 33362797 PMCID: PMC7759493 DOI: 10.3389/fimmu.2020.609063] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2020] [Accepted: 11/12/2020] [Indexed: 12/18/2022] Open
Abstract
Mesenchymal Stromal Cells (MSCs) are fibroblast-like cells of mesodermal origin present in many tissues and which have the potential to differentiate to osteoblasts, adipocytes and chondroblasts. They also have a clear immunosuppressive and tissue regeneration potential. Indeed, the initial classification of MSCs as pluripotent stem cells, has turned into their identification as stromal progenitors. Due to the relatively simple procedures available to expand in vitro large numbers of GMP grade MSCs from a variety of different tissues, many clinical trials have tested their therapeutic potential in vivo. One pathological condition where MSCs have been quite extensively tested is steroid resistant (SR) graft versus host disease (GvHD), a devastating condition that may occur in acute or chronic form following allogeneic hematopoietic stem cell transplantation. The clinical and experimental results obtained have outlined a possible efficacy of MSCs, but unfortunately statistical significance in clinical studies has only rarely been reached and effects have been relatively limited in most cases. Nonetheless, the extremely complex pathogenetic mechanisms at the basis of GvHD, the fact that studies have been conducted often in patients who had been previously treated with multiple lines of therapy, the variable MSC doses and schedules administered in different trials, the lack of validated potency assays and clear biomarkers, the difference in MSC sources and production methods may have been major factors for this lack of clear efficacy in vivo. The heterogeneity of MSCs and their different stromal differentiation potential and biological activity may be better understood through more refined single cell sequencing and proteomic studies, where either an “anti-inflammatory” or a more “immunosuppressive” profile can be identified. We summarize the pathogenic mechanisms of acute and chronic GvHD and the role for MSCs. We suggest that systematic controlled clinical trials still need to be conducted in the most promising clinical settings, using better characterized cells and measuring efficacy with specific biomarkers, before strong conclusions can be drawn about the therapeutic potential of these cells in this context. The same analysis should be applied to other inflammatory, immune or degenerative diseases where MSCs may have a therapeutic potential.
Collapse
Affiliation(s)
- Martino Introna
- Center of Cellular Therapy "G. Lanzani", Division of Haematology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy
| | - Josée Golay
- Center of Cellular Therapy "G. Lanzani", Division of Haematology, Azienda Socio-Sanitaria Territoriale Papa Giovanni XXIII, Bergamo, Italy.,Fondazione per la Ricerca Ospedale Maggiore, Bergamo, Italy
| |
Collapse
|
|
43
|
Wan L, Jin Z, Hu B, Lv K, Lei L, Liu Y, Song Y, Zhu Y, Gong H, Xu M, Du Y, Xu Y, Liu H, Wu D, Liu Y. IL-Y Aggravates Murine Chronic Graft- Versus-Host Disease by Enhancing T and B Cell Responses. Front Immunol 2020; 11:559740. [PMID: 33329519 PMCID: PMC7719702 DOI: 10.3389/fimmu.2020.559740] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 10/20/2020] [Indexed: 11/16/2022] Open
Abstract
IL-Y, a synthetic member of IL-12 cytokine family, was found to exert potent immunosuppressive effects by inhibiting the differentiation and activation of Th1 and Th17 cells. However, the role of IL-Y in the development of chronic graft-versus-host disease (cGVHD) remains unknown. Here, using murine models of scleroderma-like and lupus-like cGVHD, we examined the function of IL-Y in the pathogenesis of cGVHD by hydrodynamically injecting minicircle-IL-Y expressing plasmids (MC IL-Y). In contrast with the reported immune suppressive function of IL-Y, administration of MC IL-Y enhanced cGVHD severity reflected by deteriorated multi-organ pathologic damages. In lupus-like cGVHD model, urine protein and the serum anti-dsDNA antibody (IgG) were significantly upregulated by IL-Y treatment. Further study demonstrated that IL-Y impacts both donor T and B cell response. In T cells, IL-Y inhibited the generation of CD4+Foxp3+ regulator T (Treg) cells during the development of cGVHD. IL-Y may also increase the infiltration of pathogenic TNF-α producing CD4+ and CD8+ T cells through IL-27Rα in recipient spleens, as this effect was diminished in IL-27Rα deficient T cells. Moreover, IL-Y enhanced the differentiation of ICOS+ T follicular helper (Tfh) cells. In B cells, the percentage of germinal center (GC) B cells in recipient spleens was significantly upregulated by MC IL-Y plasmid administration. The levels of co-stimulatory molecules, MHC-II and CD86, on B cells were also enhanced by IL-Y expression. Taken together, our data indicated that IL-Y promoted the process of cGVHD by activating pathogenic T and B cells.
Collapse
Affiliation(s)
- Li Wan
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Ziqi Jin
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Bo Hu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Kangkang Lv
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Lei Lei
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yonghao Liu
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, Yoo Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Yuan Song
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, Yoo Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ying Zhu
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, Yoo Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Huanle Gong
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Mimi Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yuanyuan Du
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yang Xu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Haiyan Liu
- Immunology Programme, Life Sciences Institute and Department of Microbiology and Immunology, Yoo Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Depei Wu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| | - Yuejun Liu
- National Clinical Research Center for Hematologic Diseases, Jiangsu Institute of Hematology, The First Affiliated Hospital of Soochow University, Institute of Blood and Marrow Transplantation, Suzhou, China.,Collaborative Innovation Center of Hematology, Soochow University, Suzhou, China
| |
Collapse
|
|
44
|
Alpert O, Begun L, Garren P, Solhkhah R. Cytokine storm induced new onset depression in patients with COVID-19. A new look into the association between depression and cytokines -two case reports. Brain Behav Immun Health 2020; 9:100173. [PMID: 33163979 PMCID: PMC7606074 DOI: 10.1016/j.bbih.2020.100173] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/30/2020] [Accepted: 11/01/2020] [Indexed: 12/25/2022] Open
Abstract
Background Depression appears to be a common complication in patients during and post–COVID-19 infection. Understanding the mechanism of action of cytokines such as interleukin-6, interleukin-10 and others in depression and in cytokine storm syndrome, the core component of COVID- 19, could shine a new light on future treatment options for both disorders. Objective This review demonstrates the role of interleukins in COVID-19 pathogenesis and their role in depression. Results We described cases we have treated as an example for the dual role interleukins have in COVID-19 infection and depression and reviewed approximately 70 articles focusing on the role of interleukins in cytokine storm syndrome and depression. Conclusion This review highlights the key features of cytokines in both diseases. As the scientific community has more time to recover and process the effect of the current pandemic, we believe that additional research will pave the way to diverse pathways to treat depression in these patient and others.
This review highlights the key features of cytokines in both diseases. We believe that additional research will pave the way to diverse pathways to treat depression in COVID-19 patients and others.
Collapse
Affiliation(s)
- Orna Alpert
- Department of Psychiatry & Behavioral Health, Jersey Shore University Medical Center and Hackensack Meridian School of Medicine at Seton Hall University, United States
| | - Leonid Begun
- Department of Psychiatry, Jersey Shore University Hospital, United States
| | | | - Ramon Solhkhah
- Department of Psychiatry & Behavioral Health, Jersey Shore University Medical Center and Hackensack Meridian School of Medicine at Seton Hall University, United States
| |
Collapse
|
|
45
|
Saidu NEB, Bonini C, Dickinson A, Grce M, Inngjerdingen M, Koehl U, Toubert A, Zeiser R, Galimberti S. New Approaches for the Treatment of Chronic Graft-Versus-Host Disease: Current Status and Future Directions. Front Immunol 2020; 11:578314. [PMID: 33162993 PMCID: PMC7583636 DOI: 10.3389/fimmu.2020.578314] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 09/18/2020] [Indexed: 12/15/2022] Open
Abstract
Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.
Collapse
Affiliation(s)
- Nathaniel Edward Bennett Saidu
- Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
- Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Chiara Bonini
- Experimental Hematology Unit, San Raffaele Scientific Institute, Milano, Italy
| | - Anne Dickinson
- Haematological Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Magdalena Grce
- Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Marit Inngjerdingen
- Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway
| | - Ulrike Koehl
- Faculty of Medicine, Institute of Clinical Immunology, University Leipzig and Fraunhofer IZI, Leipzig, Germany
| | - Antoine Toubert
- Université de Paris, Institut de Recherche Saint Louis, EMiLy, Inserm U1160, Paris, France
- Laboratoire d'Immunologie et d`Histocompatibilité, AP-HP, Hopital Saint-Louis, Paris, France
| | - Robert Zeiser
- Department of Hematology, Oncology and Stem Cell Transplantation, Freiburg University Medical Center, Faculty of Medicine, Freiburg, Germany
| | - Sara Galimberti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| |
Collapse
|
|
46
|
Knobler R, Arenberger P, Arun A, Assaf C, Bagot M, Berlin G, Bohbot A, Calzavara-Pinton P, Child F, Cho A, French LE, Gennery AR, Gniadecki R, Gollnick HPM, Guenova E, Jaksch P, Jantschitsch C, Klemke C, Ludvigsson J, Papadavid E, Scarisbrick J, Schwarz T, Stadler R, Wolf P, Zic J, Zouboulis C, Zuckermann A, Greinix H. European dermatology forum - updated guidelines on the use of extracorporeal photopheresis 2020 - part 1. J Eur Acad Dermatol Venereol 2020; 34:2693-2716. [PMID: 33025659 PMCID: PMC7820969 DOI: 10.1111/jdv.16890] [Citation(s) in RCA: 53] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2020] [Accepted: 08/06/2020] [Indexed: 01/01/2023]
Abstract
Background Following the first investigational study on the use of extracorporeal photopheresis for the treatment of cutaneous T‐cell lymphoma published in 1983, this technology has received continued use and further recognition for additional earlier as well as refractory forms. After the publication of the first guidelines for this technology in the JEADV in 2014, this technology has maintained additional promise in the treatment of other severe and refractory conditions in a multi‐disciplinary setting. It has confirmed recognition in well‐known documented conditions such as graft‐versus‐host disease after allogeneic bone marrow transplantation, systemic sclerosis, solid organ transplant rejection including lung, heart and liver and to a lesser extent inflammatory bowel disease. Materials and methods In order to further provide recognized expert practical guidelines for the use of this technology for all indications, the European Dermatology Forum (EDF) again proceeded to address these questions in the hands of the recognized experts within and outside the field of dermatology. This was done using the recognized and approved guidelines of EDF for this task. All authors had the opportunity to review each contribution as it was added. Results and conclusion These updated 2020 guidelines provide at present the most comprehensive available expert recommendations for the use of extracorporeal photopheresis based on the available published literature and expert consensus opinion. The guidelines are divided in two parts: PART I covers cutaneous T‐cell lymphoma, chronic graft‐versus‐host disease and acute graft‐versus‐host disease while PART II will cover scleroderma, solid organ transplantation, Crohn's disease, use of ECP in paediatrics practice, atopic dermatitis, type 1 diabetes, pemphigus, epidermolysis bullosa acquisita and erosive oral lichen planus.
Collapse
Affiliation(s)
- R Knobler
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - P Arenberger
- Third Faculty of Medicine, Charles University, Prague, Czech Republic
| | - A Arun
- FRCPath, The Rotherham NHA Foundation Trust, Rotherham, UK
| | - C Assaf
- Department of Dermatology and Venerology, Helios Klinikum Krefeld, Krefeld, Germany
| | - M Bagot
- Hospital Saint Louis, Université de Paris, Paris, France
| | - G Berlin
- Department of Clinical Immunology and Transfusion Medicine, Linköping University, Linköping, Sweden.,Department of Biomedical and Clinical Sciences, Linköping University, Linköping, Sweden
| | - A Bohbot
- Onco-Hematology Department, Hautepierre Hospital, Strasbourg, France
| | | | - F Child
- FRCP, St John's Institution of Dermatology, Guy's and St Thomas' NHS Foundation Trust, London, UK
| | - A Cho
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - L E French
- Department of Dermatology, University Hospital, München, Germany
| | - A R Gennery
- Translational and Clinical Research Institute, Newcastle University Great North Children's Hospital Newcastle upon Tyne, Newcastle University, Newcastle upon Tyne, UK
| | - R Gniadecki
- Division of Dermatology, University of Alberta, Edmonton, AB, Canada
| | - H P M Gollnick
- Dept. Dermatology & Venereology, Otto-von-Guericke University, Magdeburg, Germany
| | - E Guenova
- Faculty of Biology and Medicine, University of Lausanne, Lausanne, Switzerland.,Department of Dermatology, Lausanne University Hospital CHUV, Lausanne, Switzerland
| | - P Jaksch
- Department of Thoracic Surgery, Medical University Vienna, Vienna, Austria
| | - C Jantschitsch
- Department of Dermatology, Medical University of Vienna, Vienna, Austria
| | - C Klemke
- Hautklinik Städtisches Klinikum Karlsruhe, Karlsruhe, Germany
| | - J Ludvigsson
- Crown Princess Victoria Children's Hospital and Division of Pediatrics, Department of Biomedical and Clinical Sciences, University Hospital, Linköping University, Linköping, Sweden
| | - E Papadavid
- National and Kapodistrian University of Athens, Athens, Greece
| | | | - T Schwarz
- Department of Dermatology, University Clinics Schleswig-Holstein, Kiel, Germany
| | - R Stadler
- University Clinic for Dermatology Johannes Wesling Medical Centre, UKRUB, University of Bochum, Minden, Germany
| | - P Wolf
- Department of Dermatology, Medical University of Graz, Graz, Austria
| | - J Zic
- Department of Dermatology, Vanderbilt University Medical Center, Nashville, TN, USA
| | - C Zouboulis
- Departments of Dermatology, Venereology, Allergology and Immunology, Dessau Medical Center, Brandenburg Medical School Theodor Fontane, Dessau, Germany
| | - A Zuckermann
- Department of Cardiac Surgery, Medical University of Vienna, Vienna, Austria
| | - H Greinix
- Division of Haematology, LKH-Univ. Klinikum Graz, Medical University of Graz, Graz, Austria
| |
Collapse
|
|
47
|
Matoba K, Takeda Y, Nagai Y, Sekiguchi K, Yokota T, Utsunomiya K, Nishimura R. The Physiology, Pathology, and Therapeutic Interventions for ROCK Isoforms in Diabetic Kidney Disease. Front Pharmacol 2020; 11:585633. [PMID: 33101039 PMCID: PMC7545791 DOI: 10.3389/fphar.2020.585633] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Accepted: 09/07/2020] [Indexed: 01/14/2023] Open
Abstract
Rho-associated coiled-coil-containing protein kinase (ROCK) is a serine/threonine kinase that was originally identified as RhoA interacting protein. A diverse array of cellular functions, including migration, proliferation, and phenotypic modulation, are orchestrated by ROCK through a mechanism involving cytoskeletal rearrangement. Mammalian cells express two ROCK isoforms: ROCK1 (Rho-kinase β/ROKβ) and ROCK2 (Rho-kinase α/ROKα). While both isoforms have structural similarities and are widely expressed across multiple tissues, investigations in gene knockout animals and cell-based studies have revealed distinct functions of ROCK1 and ROCK2. With respect to the kidney, inhibiting ROCK activity has proven effective for the preventing diabetic kidney disease (DKD) in both type 1 and type 2 diabetic rodent models. However, despite significant progress in the understanding of the renal ROCK biology over the past decade, the pathogenic roles of the ROCK isoforms is only beginning to be elucidated. Recent studies have demonstrated the involvement of renal ROCK1 in mitochondrial dynamics and cellular transdifferentiation, whereas ROCK2 activation leads to inflammation, fibrosis, and cell death in the diabetic kidney. This review provides a conceptual framework for dissecting the molecular underpinnings of ROCK-driven renal injury, focusing on the differences between ROCK1 and ROCK2.
Collapse
Affiliation(s)
- Keiichiro Matoba
- Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yusuke Takeda
- Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Yosuke Nagai
- Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kensuke Sekiguchi
- Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Tamotsu Yokota
- Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Kazunori Utsunomiya
- Center for Preventive Medicine, The Jikei University School of Medicine, Tokyo, Japan
| | - Rimei Nishimura
- Division of Diabetes, Metabolism, and Endocrinology, Department of Internal Medicine, The Jikei University School of Medicine, Tokyo, Japan
| |
Collapse
|
|
48
|
Zhang M, Zhang S. T Cells in Fibrosis and Fibrotic Diseases. Front Immunol 2020; 11:1142. [PMID: 32676074 PMCID: PMC7333347 DOI: 10.3389/fimmu.2020.01142] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/11/2020] [Indexed: 01/08/2023] Open
Abstract
Fibrosis is the extensive deposition of fibrous connective tissue, and it is characterized by the accumulation of collagen and other extracellular matrix (ECM) components. Fibrosis is essential for wound healing and tissue repair in response to a variety of triggers, which include infection, inflammation, autoimmune disorder, degenerative disease, tumor, and injury. Fibrotic remodeling in various diseases, such as liver cirrhosis, pulmonary fibrosis, renal interstitial fibrosis, myocardial infarction, systemic sclerosis (SSc), and graft-versus-host disease (GVHD), can impair organ function, causing high morbidity and mortality. Both innate and adaptive immunity are involved in fibrogenesis. Although the roles of macrophages in fibrogenesis have been studied for many years, the underlying mechanisms concerning the manner in which T cells regulate fibrosis are not completely understood. The T cell receptor (TCR) engages the antigen and shapes the repertoire of antigen-specific T cells. Based on the divergent expression of surface molecules and cell functions, T cells are subdivided into natural killer T (NKT) cells, γδ T cells, CD8+ cytotoxic T lymphocytes (CTL), regulatory T (Treg) cells, T follicular regulatory (Tfr) cells, and T helper cells, including Th1, Th2, Th9, Th17, Th22, and T follicular helper (Tfh) cells. In this review, we summarize the pro-fibrotic or anti-fibrotic roles and distinct mechanisms of different T cell subsets. On reviewing the literature, we conclude that the T cell regulations are commonly disease-specific and tissue-specific. Finally, we provide perspectives on microbiota, viral infection, and metabolism, and discuss the current advancements of technologies for identifying novel targets and developing immunotherapies for intervention in fibrosis and fibrotic diseases.
Collapse
Affiliation(s)
- Mengjuan Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| | - Song Zhang
- College of Life Sciences, Nankai University, Tianjin, China
| |
Collapse
|
|
49
|
Gonzalez RM, Pidala J. Evolving Therapeutic Options for Chronic Graft‐versus‐Host Disease. Pharmacotherapy 2020; 40:756-772. [DOI: 10.1002/phar.2427] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Revised: 04/04/2020] [Accepted: 04/13/2020] [Indexed: 12/17/2022]
Affiliation(s)
- Rebecca M. Gonzalez
- Department of Blood & Marrow Transplant and Cellular Immunotherapy (BMT CI) Moffitt Cancer Center Tampa Florida USA
- Department of Pharmacy Moffitt Cancer Center Tampa Florida USA
| | - Joseph Pidala
- Department of Blood & Marrow Transplant and Cellular Immunotherapy (BMT CI) Moffitt Cancer Center Tampa Florida USA
| |
Collapse
|
|
50
|
Winkler J, Tittlbach H, Schneider A, Buchstaller C, Mayr A, Vasova I, Roesler W, Mach M, Mackensen A, Winkler TH. Measuring the cellular memory B cell response after vaccination in patients after allogeneic stem cell transplantation. Ann Hematol 2020; 99:1895-1906. [PMID: 32519092 PMCID: PMC7340644 DOI: 10.1007/s00277-020-04072-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Accepted: 04/28/2020] [Indexed: 02/04/2023]
Abstract
After allogeneic hematopoietic stem cell transplantation (HSCT), patients are repetitively vaccinated to reduce the risk of infection caused by the immune deficiency following allogeneic HSCT. By the vaccination of transplanted patients, the humoral memory function can be restored in the majority of cases. It is unknown, however, to what extent memory B cells derived from the donor contribute to the mobilization of antibody-secreting cells and long-term humoral memory in patients after allogeneic HSCT. We therefore analyzed patients after allogeneic HSCT for memory B cell responses 7 days after single vaccination against tetanus toxoid (TT), diphtheria toxoid (DT), pertussis toxoid (PT), Haemophilus influenzae type b (Hib), and poliovirus. Patients showed an insufficient mobilization of plasmablasts (PB) after vaccination, whereas healthy subjects (HD, n = 13) exhibited a significant increase of PB in the peripheral blood. Regarding vaccine-specific antibody-secreting PB, all HD responded against all vaccine antigens, as expected. However, only 65% of the patients responded with a measurable increase in IgG-secreting PB against TT, 65% against DT, 33% against PT, and 53% against poliovirus. Correspondingly, the antibody titers on day 7 after vaccination did not increase in patients. A significant increase of serum titers for the vaccine antigens was detectable in the majority of patients only after repetitive vaccinations. In contrast to the low mobilization of vaccine-specific PB after vaccination, a high number of PB before vaccination was detectable in patients following allogeneic HSCT. High frequencies of circulating PB correlated with the incidence of moderate/severe chronic GVHD. In summary, patients showed a weak mobilization of antigen-specific PB and an inadequate increase in antibody titers 7 days after the first vaccination. Patients with moderate or severe chronic GVHD in their history had a significantly higher percentage of IgG-secreting PB prior to vaccination. The antigen specificity of these IgG-secreting PB is currently unknown.
Collapse
Affiliation(s)
- Julia Winkler
- Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Glückstrasse 6, 91054, Erlangen, Germany.
| | - Hannes Tittlbach
- Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Glückstrasse 6, 91054, Erlangen, Germany.,Department of Biology, Division of Genetics, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Andrea Schneider
- Department of Biology, Division of Genetics, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Corinna Buchstaller
- Department of Medical Informatics, Biometry, and Epidemiology, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| | - Andreas Mayr
- Department of Medical Biometry, Informatics and Epidemiology, University Hospital Bonn, Bonn, Germany
| | - Ingrid Vasova
- Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Glückstrasse 6, 91054, Erlangen, Germany
| | - Wolf Roesler
- Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Glückstrasse 6, 91054, Erlangen, Germany
| | - Michael Mach
- Institute for Clinical and Molecular Virology, University Hospital Erlangen, Erlangen, Germany
| | - Andreas Mackensen
- Department of Internal Medicine 5, Hematology/Oncology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Glückstrasse 6, 91054, Erlangen, Germany
| | - Thomas H Winkler
- Department of Biology, Division of Genetics, Nikolaus-Fiebiger-Center for Molecular Medicine, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen, Germany
| |
Collapse
|