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Wright RC, Campbell DJ, Levings MK. Pharmacotherapeutic strategies to promote regulatory T cell function in autoimmunity. Curr Opin Immunol 2025; 94:102554. [PMID: 40187268 DOI: 10.1016/j.coi.2025.102554] [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: 01/18/2025] [Revised: 03/15/2025] [Accepted: 03/17/2025] [Indexed: 04/07/2025]
Abstract
Autoimmune diseases arise when self-antigen-specific T and B cells escape central and peripheral mechanisms of tolerance. One such mechanism is control of autoreactivity by regulatory T cells (Tregs), which have an essential role in suppressing autoimmunity. Consequently, there is significant interest in developing ways to boost or restore the function of Tregs in order to prevent or treat autoimmunity, induce tolerance, and thus reduce the reliance on broadly immunosuppressive agents. Strategies include enhancing the numbers and/or function of Tregs directly in vivo or via adoptive cell therapy. Here, we review recent advances in our understanding of how pharmacologic approaches can be applied to enhance Treg function in vivo through repurposing of established drug therapies or application of new therapies. Specifically, we discuss the potential of Treg-promoting drugs, including interleukin-2 and its derivatives, and tumor necrosis factor receptor 2 agonists, as well as Treg-preserving tyrosine kinase 2 inhibitors. We discuss how co-stimulatory blockade with CTLA-4 immunoglobulin affects tolerogenic environments and consider whether lymphodepleting therapies, such as antithymocyte globulin and teplizumab, might be needed to condition the environment for better Treg-promoting effects. We focus on the potential application of Treg-promoting drugs in type 1 diabetes and draw on evidence from transplantation. With multiple pharmacotherapeutic strategies to optimize Tregs in vivo, there is significant promise for new approaches to effectively and durably induce autoimmune disease remission.
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Affiliation(s)
- Robert C Wright
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada
| | - Daniel J Campbell
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA; Department of Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
| | - Megan K Levings
- Department of Surgery, University of British Columbia, Vancouver, BC V6T 1Z4, Canada; BC Children's Hospital Research Institute, Vancouver, BC V5Z 4H4, Canada; School of Biomedical Engineering, University of British Columbia, Vancouver, BC V6T 2B9, Canada.
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Aydin-Ghormoz E, Ortiz J, Schubauer K, Koizumi N, Li MH, Faddoul G. Induction outcomes in adult kidney transplantation: Two decades of UNOS data analysis. Transpl Immunol 2025; 89:102198. [PMID: 39947488 DOI: 10.1016/j.trim.2025.102198] [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: 10/28/2024] [Revised: 02/02/2025] [Accepted: 02/09/2025] [Indexed: 02/16/2025]
Abstract
OBJECTIVES In the US, 92 % of kidney transplant recipients are treated with induction therapy. This analysis assesses the impact of induction immunosuppression on outcomes such as graft failure, patient mortality, and length of hospitalization. MATERIAL AND METHODS Retrospective analysis of the UNOS database in adults who received a kidney transplant from January 2000 to June 2022. Analysis focused on induction regimens including anti-thymocyte globulin (ATG), alemtuzumab and basiliximab with maintenance immunosuppression of calcineurin inhibitors, mycophenolate with or without prednisone. Multivariable logistic regression was performed to identify factors correlating with outcomes. Kaplan-Meier product limit method assessed survival. RESULTS Alemtuzumab correlated with increased graft failure in deceased-donor and living-donor kidney transplants (HR 1.075 [1.015-1.138] p = 0.013 and HR 1.096 [1.011-1.188] p = 0.026 respectively) and with increased mortality in living-donor kidney transplants (HR 1.215 [1.107-1.332] p < 0.001). Steroids maintenance was associated with fewer acute rejections in both deceased-donor and living-donor kidney transplants (HR = 0.875 [0.84-0.90] p < 0.001 and HR = 0.88 [0.83-0.93] p < 0.001 respectively). Odds of CMV was lower with alemtuzumab. Induction with alemtuzumab was associated with shorter length of stay in both deceased-donor and living-donor kidney transplants and longer time to first hospitalization in living-donor kidney transplants compared to ATG. CONCLUSIONS Alemtuzumab correlated with shorter length of stay, fewer re-hospitalizations and less CMV infections. However, it was associated with higher odds of graft failure and mortality in adult kidney transplant recipients.
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Affiliation(s)
- Emmanuel Aydin-Ghormoz
- Department of Medicine, Division of Nephrology and Hypertension, Albany Medical Center, Albany, NY, United States of America.
| | - Jorge Ortiz
- Department of General Surgery, Garnet Health Medical Center, Middletown, NY, United States of America
| | - Kathryn Schubauer
- College of Medicine and Life Sciences, University of Toledo, Toledo, OH, United States of America
| | - Naoru Koizumi
- Schar School of Policy and Government, George Mason University, Arlington, VA, United States of America
| | - Meng-Hao Li
- Schar School of Policy and Government, George Mason University, Arlington, VA, United States of America
| | - Geovani Faddoul
- Department of Medicine, Division of Nephrology and Hypertension, Albany Medical Center, Albany, NY, United States of America
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Mohty R, Al Kadhimi Z, Kharfan-Dabaja M. Post-transplant cyclophosphamide or cell selection in haploidentical allogeneic hematopoietic cell transplantation? Hematology 2024; 29:2326384. [PMID: 38597828 DOI: 10.1080/16078454.2024.2326384] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Accepted: 02/28/2024] [Indexed: 04/11/2024] Open
Abstract
BACKGROUND One major limitation for broader applicability of allogeneic hematopoietic cell transplantation (allo-HCT) in the past was the lack of HLA-matched histocompatible donors. Preclinical mouse studies using T-cell depleted haploidentical grafts led to an increased interest in the use of ex vivo T-cell depleted (TCD) haploidentical allo-HCT. TCD grafts through negative (T-cell depletion) or positive (CD34+ cell selection) techniques have been investigated to reduce the risk of graft-versus-host disease (GVHD) given the known implications of alloreactive T cells. A more practical approach to deplete alloreactive T cells in vivo using high doses of cyclophosphamide after allografting has proved to be feasible in overcoming the HLA barrier. Such approach has extended allo-HCT feasibility to patients for whom donors could not be found in the past. Nowadays, haploidentical donors represent a common donor source for patients in need of an allo-HCT. The broad application of haploidentical donors became possible by understanding the importance of depleting alloreactive donor T cells to facilitate engraftment and reduce incidence and severity of GVHD. These techniques involve ex vivo graft manipulation or in vivo utilization of pharmacologic agents, notably post-transplant cyclophosphamide (PTCy). DISCUSSION While acknowledging that no randomized controlled prospective studies have been yet conducted comparing TCD versus PTCy in haploidentical allo-HCT recipients, there are two advantages that would favor the PTCy, namely ease of application and lower cost. However, emerging data on adverse events associated with PTCy including, but not limited to cardiac associated toxicities or increased incidence of post-allograft infections, and others, are important to recognize.
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Affiliation(s)
- Razan Mohty
- Division of Hematology Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Zaid Al Kadhimi
- Division of Hematology Oncology, Department of Medicine, O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham Heersink School of Medicine, Birmingham, AL, USA
| | - Mohamed Kharfan-Dabaja
- Division of Hematology-Oncology, Blood and Marrow Transplantation Program, Mayo Clinic, Jacksonville, FL, USA
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Iftikhar R, DeFilipp Z, DeZern AE, Pulsipher MA, Bejanyan N, Burroughs LM, Kharfan-Dabaja MA, Arai S, Kassim A, Nakamura R, Saldaña BJD, Aljurf M, Hamadani M, Carpenter PA, Antin JH. Allogeneic Hematopoietic Cell Transplantation for the Treatment of Severe Aplastic Anemia: Evidence-Based Guidelines From the American Society for Transplantation and Cellular Therapy. Transplant Cell Ther 2024; 30:1155-1170. [PMID: 39307421 DOI: 10.1016/j.jtct.2024.09.017] [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: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 10/10/2024]
Abstract
Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment for severe aplastic anemia (SAA). Existing guidance about HCT in SAA is primarily derived from expert reviews, registry data and societal guidelines; however, transplant-specific guidelines for SAA are lacking. A panel of SAA experts, both pediatric and adult transplant physicians, developed consensus recommendations using Grading of Recommendation, Assessment, Development, and Evaluation (GRADE) methodology employing a GRADE guideline development tool. The panel agrees with previous recommendations for the preferential use of bone marrow as a graft source and the use of rabbit over horse antithymocyte globulin (ATG) for HCT conditioning. Fludarabine containing regimens are preferred for patients at high risk of graft failure and those receiving matched unrelated or haploidentical donor transplant. Given advancements in HCT, the panel does not endorse the historical 40-year age cut-off for considering upfront HCT in adults, acknowledging that fit older patients may also benefit from HCT. The panel also endorses increased utilization of HCT by prioritizing matched unrelated or haploidentical donor HCT over immunosuppressive therapy in children and adults who lack a matched related donor. Finally, the panel suggests either calcineurin inhibitor plus methotrexate or post-transplant cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis for matched related or matched unrelated donor recipients. These recommendations reflect a significant advancement in transplant strategies for SAA and highlight the importance of ongoing and further research to revisit current evidence in terms of donor choice, conditioning chemotherapy, GVHD prophylaxis and post-transplant immunosuppression.
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Affiliation(s)
- Raheel Iftikhar
- Armed Forces Bone Marrow Transplant Center, National University of Medical Sciences, Rawalpindi, Pakistan.
| | - Zachariah DeFilipp
- Hematopoietic Cell Transplant and Cell Therapy Program, Massachusetts General Hospital, Boston, Massachusetts
| | - Amy E DeZern
- Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland
| | - Michael A Pulsipher
- Division of Pediatric Hematology and Oncology, Intermountain Primary Children's Hospital, Huntsman Cancer Institute, Spencer Fox Eccles School of Medicine at the University of Utah, Salt Lake City, UT
| | - Nelli Bejanyan
- Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida
| | - Lauri M Burroughs
- Fred Hutchinson Cancer Center, Clinical Research Division and University of Washington, Seattle, Washington
| | - Mohamed A Kharfan-Dabaja
- Division of Hematology-Oncology, Blood and Marrow Transplantation and Cellular Therapy Program, Mayo Clinic, Jacksonville, Florida
| | - Sally Arai
- Division of BMT and Cell Therapy, Department of Medicine, Stanford University Medical Center, Stanford, California
| | - Adetola Kassim
- Division of Hematology/Oncology, The Vanderbilt Clinic, Nashville, Tennessee
| | - Ryotaro Nakamura
- Department of Hematology and Hematopoietic Cell Transplantation, City of Hope, Duarte, California
| | - Blachy J Dávila Saldaña
- Division of Blood and Marrow Transplantation, Children's National Hospital, Washington District of Columbia
| | - Mahmoud Aljurf
- Adult Hematology and Stem Cell Transplant, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Mehdi Hamadani
- Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Paul A Carpenter
- Fred Hutchinson Cancer Center, Clinical Research Division and University of Washington, Seattle, Washington
| | - Joseph H Antin
- Dana-Farber Cancer Institute/Brigham and Women's Hospital, Boston, Massachusetts
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Xu Y, Wang X, Hu Z, Huang R, Yang G, Wang R, Yang S, Guo L, Song Q, Wei J, Zhang X. Advances in hematopoietic stem cell transplantation for autoimmune diseases. Heliyon 2024; 10:e39302. [PMID: 39492896 PMCID: PMC11530805 DOI: 10.1016/j.heliyon.2024.e39302] [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: 07/21/2024] [Revised: 09/14/2024] [Accepted: 10/10/2024] [Indexed: 11/05/2024] Open
Abstract
Autoimmune diseases (ADs) are a collection of immunological disorders in which the immune system responds to self-antigens by producing autoantibodies or self-sensitized cells. Current treatments are unable to cure ADs, and achieving long-term drug-free remission remains a challenging task. Hematopoietic stem cell transplantation (HSCT) stands out from other therapies by specifically targeting ADs that target various cell subpopulations, demonstrating notable therapeutic benefits and resulting in sustained drug-free remission. Since different ADs have distinct mechanisms of action, the comprehensive understanding of how HSCT works in treating ADs is crucial. This review provides a detailed overview of the latest research and clinical applications of HSCT in treating ADs, offering new insights for clinicians aiming to optimize its use for ADs management.
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Affiliation(s)
- Yuxi Xu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Xiaoqi Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Ziyi Hu
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Ruihao Huang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Guancui Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Rui Wang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Shijie Yang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Liyan Guo
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
| | - Qingxiao Song
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
| | - Jin Wei
- Department of Hematology, Affiliated Hospital of North Sichuan Medical College, Sichuan, 637000, China
| | - Xi Zhang
- Medical Center of Hematology, Xinqiao Hospital of Army Medical University, Chongqing, 400037, China
- Chongqing Key Laboratory of Hematology and Microenvironment, Chongqing, 400037, China
- Jinfeng Laboratory, Chongqing, 401329, China
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Freitas GRR, Fernandes MDL, Agena F, Lemos FBC, de Paula FJ, Coelho V, David-Neto E, Galante NZ. Effects of two immunosuppression regimens on T-lymphocyte subsets in elderly kidney transplant recipients. Front Immunol 2024; 15:1405855. [PMID: 39372414 PMCID: PMC11449757 DOI: 10.3389/fimmu.2024.1405855] [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: 03/24/2024] [Accepted: 08/06/2024] [Indexed: 10/08/2024] Open
Abstract
Background Despite the growing number of elderly kidney transplant (Ktx) recipients, few studies have examined the effects of immunosuppression on their lymphocyte profiles. Methods We evaluated the early conversion from mycophenolate sodium (MPS) to everolimus (EVL) after rabbit antithymocyte globulin (rATG) 2 mg/kg induction in elderly kidney recipients. Three groups of KTx patients were compared: (a) Young (n=20, 36 ± 7 y) receiving standard immunosuppression (Group A1) (prednisone, tacrolimus, and MPS), (b) Elderly (n=35, 65 ± 3 y) receiving standard immunosuppression (Group B1), and (c) Elderly (n=16, 65 ± 3 y) with early (mean 30 d) conversion from MPS to EVL (Group B2). Naive, memory, and regulatory peripheral blood TCD4+ lymphocytes were quantified at 0, 30, and 365 d. Results Results are reported as [mean(p25-p75)]. Young recipients had higher lymphocyte counts at baseline [2,100(1,630-2,400) vs. 1,310 (1,000-1,600)/mm3, p<0.0001] maintained higher counts within 365 d [1,850(1,590-2,120) vs. 1,130(460-1,325)/mm3, p=0.018 and vs. 1,410(805-1,895)/mm3, p=0.268]. Elderly recipients showed a decrease in lymphocytes within 30 d [1,310(1,000-1,600) vs. 910(700-1,198)/mm3, p=0.0012] with recovery within 365 d. The same pattern was observed in total lymphocytes and TCD4+ counts. Rabbit antithymocyte globulin induced a reduction in central memory T-cell percentages at 30 d in both young recipients [6.2(3.77-10.8) vs. 5.32(2.49-7.28)% of CD4+, p=0.036] and in elderly recipients [8.17(5.28-12.88) vs. 6.74(4.36-11)% of CD4+, p=0.05] on standard immunosuppression, returning to baseline at 365 d in elderly recipients but not in young recipients. Regulatory T CD39+ cells (Treg) percentages decreased at 30 d in elderly recipients [2.1(1.23-3.51) vs. 1.69(0.8-2.66)% of CD4+, p=0.0028] and in young recipients [1.29(0.45-1.85) vs. 0.84(0.18-1.82)% of CD4+, p=0.0038], returning to baseline at 365 d in elderly recipients [2.1(1.23-3.51) vs. 2.042(0.88-2.42)% of CD4+], but not in young recipients [1.29(0.45-1.85) vs. 0.86(0.7-1.34) % of CD4+]. The elderly everolimus conversion group did not show significant changes in cell profile over time or compared to elderly recipients with standard immunosuppression. Conclusion Aging favored the maintenance of Treg during the late transplantation period despite ongoing immunosuppression. Lymphocyte depletion due to rATG was more prominent in elderly recipients and affected memory subsets with a temporary reduction in central memory T cells. However, conversion to everolimus did not impact Treg profile. Reducing the dose of rATG in elderly recipients seems necessary for the expected lymphocyte changes with EVL to occur. Clinical trial registration nEverOld Trial, identifier NTC01631058.
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Affiliation(s)
- Geraldo Rubens R. Freitas
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Departamento de transplante renal, Hospital Universitário de Brasília (HUB), Empresa Brasileira de Serviços Hospitalares (EBSERH), Brasília, Brazil
| | - Maria da Luz Fernandes
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Fabiana Agena
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Francine B. C. Lemos
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Flavio J. de Paula
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Verônica Coelho
- Laboratório de Imunologia, Instituto do Coração, Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Laboratório de Investigação Médica 19 (LIM-19), Hospital das Clínicas HCFMUSP, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
- Instituto de Investigação em Imunologia, Instituto Nacional de Ciência e Tecnologia (iii-INCT), São Paulo, Brazil
| | - Elias David-Neto
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
| | - Nelson Z. Galante
- Serviço de Transplante Renal, Hospital das Clínicas, Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil
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Shimano KA, Rothman JA, Allen SW, Castillo P, de Jong JLO, Dror Y, Geddis AE, Lau BW, McGuinn C, Narla A, Overholt K, Pereda MA, Sharathkumar A, Sasa G, Nakano TA, Myers K, Gloude NJ, Broglie L, Boklan J. Treatment of newly diagnosed severe aplastic anemia in children: Evidence-based recommendations. Pediatr Blood Cancer 2024; 71:e31070. [PMID: 38757488 DOI: 10.1002/pbc.31070] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2024] [Revised: 04/27/2024] [Accepted: 04/29/2024] [Indexed: 05/18/2024]
Abstract
Severe aplastic anemia (SAA) is a rare potentially fatal hematologic disorder. Although overall outcomes with treatment are excellent, there are variations in management approach, including differences in treatment between adult and pediatric patients. Certain aspects of treatment are under active investigation in clinical trials. Because of the rarity of the disease, some pediatric hematologists may have relatively limited experience with the complex management of SAA. The following recommendations reflect an up-to-date evidence-based approach to the treatment of children with newly diagnosed SAA.
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Affiliation(s)
- Kristin A Shimano
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplant, University of California San Francisco Benioff Children's Hospital, San Francisco, California, USA
| | - Jennifer A Rothman
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Duke University Medical Center, Durham, North Carolina, USA
| | - Steven W Allen
- Department of Pediatrics, Pediatric Hematology/Oncology, University of Pittsburgh School of Medicine, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA
| | - Paul Castillo
- Department of Pediatrics, Division of Pediatric Hematology Oncology, UF Health Shands Children's Hospital, Gainesville, Florida, USA
| | - Jill L O de Jong
- Department of Pediatrics, Section of Hematology/Oncology/Stem Cell Transplantation, University of Chicago, Chicago, Illinois, USA
| | - Yigal Dror
- Department of Pediatrics, Marrow Failure and Myelodysplasia Program, Division of Hematology/Oncology, The Hospital for Sick Children, Toronto, Canada
| | - Amy E Geddis
- Department of Pediatrics, Cancer and Blood Disorders Center, Seattle Children's Hospital, Seattle, Washington, USA
| | - Bonnie W Lau
- Department of Pediatrics, Pediatric Hematology-Oncology, Dartmouth-Hitchcock, Lebanon, New Hampshire, USA
| | - Catherine McGuinn
- Department of Pediatrics, Division of Pediatric Hematology Oncology, Weill Cornell Medicine, New York, New York, USA
| | - Anupama Narla
- Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA
| | - Kathleen Overholt
- Department of Pediatrics, Pediatric Hematology/Oncology, Riley Hospital for Children at Indiana University, Indianapolis, Indiana, USA
| | - Maria A Pereda
- Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Anjali Sharathkumar
- Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa, USA
| | - Ghadir Sasa
- Sarah Cannon Transplant and Cellular Therapy Network, San Antonio, Texas, USA
| | - Taizo A Nakano
- Department of Pediatrics, Center for Cancer and Blood Disorders, Children's Hospital Colorado, Aurora, Colorado, USA
| | - Kasiani Myers
- Department of Pediatrics, University of Cincinnati College of Medicine, Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA
| | - Nicholas J Gloude
- Department of Pediatrics, University of California San Diego, Rady Children's Hospital, San Diego, California, USA
| | - Larisa Broglie
- Department of Pediatric Hematology/Oncology/Blood and Marrow Transplantation, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Jessica Boklan
- Department of Pediatrics, Center for Cancer and Blood Disorders, Phoenix Children's Hospital, Phoenix, Arizona, USA
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8
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Mikami N, Sakaguchi S. Regulatory T cells in autoimmune kidney diseases and transplantation. Nat Rev Nephrol 2023; 19:544-557. [PMID: 37400628 DOI: 10.1038/s41581-023-00733-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/30/2023] [Indexed: 07/05/2023]
Abstract
Regulatory T (Treg) cells that express the transcription factor forkhead box protein P3 (FOXP3) are naturally present in the immune system and have roles in the maintenance of immunological self-tolerance and immune system and tissue homeostasis. Treg cells suppress T cell activation, expansion and effector functions by various mechanisms, particularly by controlling the functions of antigen-presenting cells. They can also contribute to tissue repair by suppressing inflammation and facilitating tissue regeneration, for example, via the production of growth factors and the promotion of stem cell differentiation and proliferation. Monogenic anomalies of Treg cells and genetic variations of Treg cell functional molecules can cause or predispose patients to the development of autoimmune diseases and other inflammatory disorders, including kidney diseases. Treg cells can potentially be utilized or targeted to treat immunological diseases and establish transplantation tolerance, for example, by expanding natural Treg cells in vivo using IL-2 or small molecules or by expanding them in vitro for adoptive Treg cell therapy. Efforts are also being made to convert antigen-specific conventional T cells into Treg cells and to generate chimeric antigen receptor Treg cells from natural Treg cells for adoptive Treg cell therapies with the aim of achieving antigen-specific immune suppression and tolerance in the clinic.
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Affiliation(s)
- Norihisa Mikami
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan
| | - Shimon Sakaguchi
- Laboratory of Experimental Immunology, Immunology Frontier Research Center, Osaka University, Osaka, Japan.
- Institute for Life and Medical Sciences, Kyoto University, Kyoto, Japan.
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9
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Cassano A, Chong AS, Alegre ML. Tregs in transplantation tolerance: role and therapeutic potential. FRONTIERS IN TRANSPLANTATION 2023; 2:1217065. [PMID: 38993904 PMCID: PMC11235334 DOI: 10.3389/frtra.2023.1217065] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Accepted: 08/14/2023] [Indexed: 07/13/2024]
Abstract
CD4+ Foxp3+ regulatory T cells (Tregs) are indispensable for preventing autoimmunity, and they play a role in cancer and transplantation settings by restraining immune responses. In this review, we describe evidence for the importance of Tregs in the induction versus maintenance of transplantation tolerance, discussing insights into mechanisms of Treg control of the alloimmune response. Further, we address the therapeutic potential of Tregs as a clinical intervention after transplantation, highlighting engineered CAR-Tregs as well as expansion of donor and host Tregs.
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Affiliation(s)
- Alexandra Cassano
- Department of Medicine, University of Chicago, Chicago, IL, United States
| | - Anita S. Chong
- Department of Surgery, University of Chicago, Chicago, IL, United States
| | - Maria-Luisa Alegre
- Department of Medicine, University of Chicago, Chicago, IL, United States
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Jacobsen LM, Diggins K, Blanchfield L, McNichols J, Perry DJ, Brant J, Dong X, Bacher R, Gersuk VH, Schatz DA, Atkinson MA, Mathews CE, Haller MJ, Long SA, Linsley PS, Brusko TM. Responders to low-dose ATG induce CD4+ T cell exhaustion in type 1 diabetes. JCI Insight 2023; 8:e161812. [PMID: 37432736 PMCID: PMC10543726 DOI: 10.1172/jci.insight.161812] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Accepted: 07/06/2023] [Indexed: 07/12/2023] Open
Abstract
BACKGROUNDLow-dose anti-thymocyte globulin (ATG) transiently preserves C-peptide and lowers HbA1c in individuals with recent-onset type 1 diabetes (T1D); however, the mechanisms of action and features of the response remain unclear. Here, we characterized the post hoc immunological outcomes of ATG administration and their potential use as biomarkers of metabolic response to therapy (i.e., improved preservation of endogenous insulin production).METHODSWe assessed gene and protein expression, targeted gene methylation, and cytokine concentrations in peripheral blood following treatment with ATG (n = 29), ATG plus granulocyte colony-stimulating factor (ATG/G-CSF, n = 28), or placebo (n = 31).RESULTSTreatment with low-dose ATG preserved regulatory T cells (Tregs), as measured by stable methylation of FOXP3 Treg-specific demethylation region (TSDR) and increased proportions of CD4+FOXP3+ Tregs (P < 0.001) identified by flow cytometry. While treatment effects were consistent across participants, not all maintained C-peptide. Responders exhibited a transient rise in IL-6, IP-10, and TNF-α (P < 0.05 for all) 2 weeks after treatment and a durable CD4+ exhaustion phenotype (increased PD-1+KLRG1+CD57- on CD4+ T cells [P = 0.011] and PD1+CD4+ Temra MFI [P < 0.001] at 12 weeks, following ATG and ATG/G-CSF, respectively). ATG nonresponders displayed higher proportions of senescent T cells (at baseline and after treatment) and increased methylation of EOMES (i.e., less expression of this exhaustion marker).CONCLUSIONAltogether in these exploratory analyses, Th1 inflammation-associated serum and CD4+ exhaustion transcript and cellular phenotyping profiles may be useful for identifying signatures of clinical response to ATG in T1D.TRIAL REGISTRATIONClinicalTrials.gov NCT02215200.FUNDINGThe Leona M. and Harry B. Helmsley Charitable Trust (2019PG-T1D011), the NIH (R01 DK106191 Supplement, K08 DK128628), NIH TrialNet (U01 DK085461), and the NIH NIAID (P01 AI042288).
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Affiliation(s)
- Laura M. Jacobsen
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Kirsten Diggins
- Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Lori Blanchfield
- Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - James McNichols
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Daniel J. Perry
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Jason Brant
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Xiaoru Dong
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
- Department of Biostatistics, University of Florida, Gainesville, Florida, USA
| | - Rhonda Bacher
- Department of Biostatistics, University of Florida, Gainesville, Florida, USA
| | - Vivian H. Gersuk
- Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Desmond A. Schatz
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - Mark A. Atkinson
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Clayton E. Mathews
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
| | - Michael J. Haller
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
| | - S. Alice Long
- Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Peter S. Linsley
- Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA
| | - Todd M. Brusko
- Department of Pediatrics, College of Medicine, University of Florida, Gainesville, Florida, USA
- Department of Pathology, Immunology, and Laboratory Medicine, University of Florida Diabetes Institute, Gainesville, Florida, USA
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11
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Chakupurakal G, Freudenberger P, Skoetz N, Ahr H, Theurich S. Polyclonal anti-thymocyte globulins for the prophylaxis of graft-versus-host disease after allogeneic stem cell or bone marrow transplantation in adults. Cochrane Database Syst Rev 2023; 6:CD009159. [PMID: 37341189 PMCID: PMC10284458 DOI: 10.1002/14651858.cd009159.pub3] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 06/22/2023]
Abstract
BACKGROUND Allogeneic haematopoietic stem cell transplantation (SCT) is an established treatment for many malignant and non-malignant haematological disorders. Graft-versus-host disease (GVHD), a condition frequently occurring after an allogeneic SCT, is the result of host tissues being attacked by donor immune cells. It affects more than half of the patients after transplant either as acute and or chronic GVHD. One strategy for the prevention of GVHD is the administration of anti-thymocyte globulins (ATGs), a set of polyclonal antibodies directed against a variety of immune cell epitopes, leading to immunosuppression and immunomodulation. OBJECTIVES To assess the effect of ATG used for the prevention of GVHD in patients undergoing allogeneic SCT with regard to overall survival, incidence and severity of acute and chronic GVHD, incidence of relapse, non-relapse mortality, graft failure and adverse events. SEARCH METHODS For this update we searched the CENTRAL, MEDLINE, Embase, trial registers and conference proceedings on the 18th November 2022 along with reference checking and contacting study authors to identify additional studies. We did not apply language restrictions. SELECTION CRITERIA We included randomised controlled trials (RCTs) investigating the impact of ATG on GVHD prophylaxis in adults suffering from haematological diseases and undergoing allogeneic SCT. The selection criteria were modified from the previous version of this review. Paediatric studies and studies where patients aged < 18 years constituted more than 20 % of the total number were excluded. Treatment arms had to differ only in the addition of ATG to the standard GVHD prophylaxis regimen. DATA COLLECTION AND ANALYSIS We used standard methodological procedures expected by the Cochrane Collaboration for data collection, extraction and analyses. MAIN RESULTS For this update we included seven new RCTs, leading to a total of ten studies investigating 1413 participants. All patients had a haematological condition which warranted an allogeneic SCT. The risk of bias was estimated as low for seven and unclear for three studies. ATG probably has little or no influence on overall survival (HR (hazard ratio) 0.93 (95 % confidence interval (CI) 0.77 to 1.13, nine studies, n = 1249, moderate-certainty evidence)). Estimated absolute effect: 430 surviving people per 1000 people not receiving ATG compared to 456 people surviving per 1000 people receiving the intervention (95 % CI 385 to 522 per 1000 people). ATG results in a reduction in acute GVHD II to IV with relative risk (RR) 0.68 (95 % CI 0.60 to 0.79, 10 studies, n = 1413, high-certainty evidence). Estimated absolute effect: 418 acute GVHD II to IV per 1000 people not receiving ATG compared to 285 per 1000 people receiving the intervention (95 % CI 251 to 331 per 1000 people). Addition of ATG results in a reduction of overall chronic GvHD with a RR of 0.53 (95 % CI 0.45 to 0.61, eight studies, n = 1273, high-certainty evidence). Estimated absolute effect: 506 chronic GVHD per 1000 people not receiving ATG compared to 268 per 1000 people receiving the intervention (95 % CI 228 to 369 per 1000 people). Further data on severe acute GVHD and extensive chronic GVHD are available in the manuscript. ATG probably slightly increases the incidence of relapse with a RR of 1.21 (95 % CI 0.99 to 1.49, eight studies, n =1315, moderate-certainty evidence). Non relapse mortality is probably slightly or not affected by ATG with an HR of 0.86 (95 % CI 0.67 to 1.11, nine studies, n=1370, moderate-certainty evidence). ATG prophylaxis may result in no increase in graft failure with a RR of 1.55 (95 % CI 0.54 to 4.44, eight studies, n = 1240, low-certainty evidence). Adverse events could not be analysed due to the serious heterogeneity in the reporting between the studies, which limited comparability (moderate-certainty evidence) and are reported in a descriptive manner. Subgroup analyses on ATG types, doses and donor type are available in the manuscript. AUTHORS' CONCLUSIONS This systematic review suggests that the addition of ATG during allogeneic SCT probably has little or no influence on overall survival. ATG results in a reduction in the incidence and severity of acute and chronic GvHD. ATG intervention probably slightly increases the incidence of relapse and probably does not affect the non relapse mortality. Graft failure may not be affected by ATG prophylaxis. Analysis of data on adverse events was reported in a narrative manner. A limitation for the analysis was the imprecision in reporting between the studies thereby reducing the confidence in the certainty of evidence.
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Affiliation(s)
- Geothy Chakupurakal
- Praxis for Haematology and Oncology, Koblenz, Germany
- Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine at the University of Cologne, Cologne, Germany
| | | | - Nicole Skoetz
- Cochrane Cancer, Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
| | - Hans Ahr
- Rheinland Klinikum, Dormagen, Germany
| | - Sebastian Theurich
- Department of Medicine III, University Hospital LMU, Ludwig-Maximilians-Universität München, Munich, Germany
- Cancer and Immunometabolism Research Group, Gene Center LMU, Munich, Germany
- German Cancer Consortium (DKTK), Munich Site , German Cancer Research Center, Heidelberg, Germany
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12
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Li N, Zhao C, Ma R, Lou R, Liu XJ, Zheng FM, Wang JZ, Wang Y, Huang XJ, Sun YQ. Cytokine profiling during conditioning in haploidentical stem cell transplantation and its prognostic impact on early transplant outcomes. Transpl Immunol 2023; 78:101830. [PMID: 36972853 DOI: 10.1016/j.trim.2023.101830] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2022] [Revised: 03/17/2023] [Accepted: 03/23/2023] [Indexed: 03/28/2023]
Abstract
Cytokine storm development is a major cause of many transplant-related complications, especially during the conditioning regimen. This study aimed to characterize the cytokine profile and determine its prognostic impact during conditioning in patients undergoing subsequent haploidentical stem cell transplantation. A total of 43 patients were enrolled in this study. Sixteen cytokines associated with cytokine release syndrome (CRS) during anti-thymocyte globulin (ATG) treatment were quantified in patients undergoing haploidentical stem cell transplantation. Thirty-six (83.7%) patients developed CRS during ATG treatment; most of those cases (33/36; 91.7%) were classified as grade 1 CRS, whereas only three (7.0%) developed grade 2 CRS. CRS was observed more frequently on the first (15/43; 34.9%) and second day (30/43; 69.8%) of ATG infusion. No factors were identified that could predict the development of CRS on the first day of ATG treatment. Five of the 16 cytokines (interleukins 6, 8, and 10 (IL-6, IL-8, and IL-10), C-reactive protein (CRP), and procalcitonin (PCT)) were significantly elevated during ATG treatment, although only the level of IL-6, IL-10, and PCT were associated with the severity of CRS. However, neither CRS nor the cytokine levels significantly impacted the development of acute graft-versus-host disease (GVHD) or cytomegalovirus (CMV) infection or affected overall survival.
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Affiliation(s)
- Na Li
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Chen Zhao
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Rui Ma
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Rui Lou
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Xiu-Juan Liu
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Feng-Mei Zheng
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Jing-Zhi Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Yu Wang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China
| | - Xiao-Jun Huang
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China; Peking-Tsinghua Center for Life Sciences, Beijing, PR China
| | - Yu-Qian Sun
- Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, PR China; Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation for the Treatment of Hematological Diseases, Beijing, PR China.
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13
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Rousse J, Royer PJ, Evanno G, Lheriteau E, Ciron C, Salama A, Shneiker F, Duchi R, Perota A, Galli C, Cozzi E, Blancho G, Duvaux O, Brouard S, Soulillou JP, Bach JM, Vanhove B. LIS1, a glyco-humanized swine polyclonal anti-lymphocyte globulin, as a novel induction treatment in solid organ transplantation. Front Immunol 2023; 14:1137629. [PMID: 36875084 PMCID: PMC9978386 DOI: 10.3389/fimmu.2023.1137629] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Accepted: 02/03/2023] [Indexed: 02/18/2023] Open
Abstract
Anti-thymocyte or anti-lymphocyte globulins (ATGs/ALGs) are immunosuppressive drugs used in induction therapies to prevent acute rejection in solid organ transplantation. Because animal-derived, ATGs/ALGs contain highly immunogenic carbohydrate xenoantigens eliciting antibodies that are associated with subclinical inflammatory events, possibly impacting long-term graft survival. Their strong and long-lasting lymphodepleting activity also increases the risk for infections. We investigated here the in vitro and in vivo activity of LIS1, a glyco-humanized ALG (GH-ALG) produced in pigs knocked out for the two major xeno-antigens αGal and Neu5Gc. It differs from other ATGs/ALGs by its mechanism of action excluding antibody-dependent cell-mediated cytotoxicity and being restricted to complement-mediated cytotoxicity, phagocyte-mediated cytotoxicity, apoptosis and antigen masking, resulting in profound inhibition of T-cell alloreactivity in mixed leucocyte reactions. Preclinical evaluation in non-human primates showed that GH-ALG dramatically reduced CD4+ (p=0.0005,***), CD8+ effector T cells (p=0.0002,***) or myeloid cells (p=0.0007,***) but not T-reg (p=0.65, ns) or B cells (p=0.65, ns). Compared with rabbit ATG, GH-ALG induced transient depletion (less than one week) of target T cells in the peripheral blood (<100 lymphocytes/L) but was equivalent in preventing allograft rejection in a skin allograft model. The novel therapeutic modality of GH-ALG might present advantages in induction treatment during organ transplantation by shortening the T-cell depletion period while maintaining adequate immunosuppression and reducing immunogenicity.
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Affiliation(s)
| | | | | | | | - Carine Ciron
- Research and Development, Xenothera, Nantes, France
| | - Apolline Salama
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | | | - Roberto Duchi
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Andrea Perota
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Cesare Galli
- Transplantation Immunology Unit, Padua University Hospital, Padova, Italy
| | - Emmanuele Cozzi
- Avantea, Laboratorio di Tecnologie della Riproduzione, Cremona, Italy
| | - Gilles Blancho
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Odile Duvaux
- Research and Development, Xenothera, Nantes, France
| | - Sophie Brouard
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
| | - Jean-Paul Soulillou
- Nantes Université, Inserm, University Hospital Center CHU Nantes, Center for Research in Transplantation and Translational Immunology, UMR 1064, ITUN, Nantes, France
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14
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Copic D, Direder M, Klas K, Bormann D, Laggner M, Ankersmit HJ, Mildner M. Antithymocyte Globulin Inhibits CD8 + T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. Cells 2023; 12:cells12030382. [PMID: 36766722 PMCID: PMC9913606 DOI: 10.3390/cells12030382] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/12/2023] [Accepted: 01/17/2023] [Indexed: 01/22/2023] Open
Abstract
BACKGROUND Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. METHODS We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. FINDINGS Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8+ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. INTERPRETATION Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.
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Affiliation(s)
- Dragan Copic
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Martin Direder
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Katharina Klas
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Daniel Bormann
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Maria Laggner
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
| | - Hendrik Jan Ankersmit
- Department of Thoracic Surgery, Laboratory for Cardiac and Thoracic Diagnosis and Regeneration, Medical University of Vienna, Waehringer Guertel 18-20, 1090 Vienna, Austria
- Correspondence: (H.J.A.); (M.M.); Tel.: +43-(0)1-40400-67770 (H.J.A.); +43-(0)1-40400-73507 (M.M.)
| | - Michael Mildner
- Department of Dermatology, Medical University of Vienna, Lazarettgasse 14, 1090 Vienna, Austria
- Correspondence: (H.J.A.); (M.M.); Tel.: +43-(0)1-40400-67770 (H.J.A.); +43-(0)1-40400-73507 (M.M.)
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15
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Jacobsen N, Frisch T, Keiding N, Heilmann C, Sengeløv H, Madsen HO, Dickmeiss E, Ryder LP. Higher recipient pre-transplant FOXP3 mRNA expression is associated with acute leukaemia relapse after HSCT. EJHAEM 2022; 3:975-979. [PMID: 36051013 PMCID: PMC9421961 DOI: 10.1002/jha2.438] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/14/2022] [Revised: 03/24/2022] [Accepted: 03/26/2022] [Indexed: 06/15/2023]
Abstract
The effect of higher FOXP3 mRNA expression by recipient pre-transplant CD4+ T cells on leukaemia relapse was analysed in a series of 106 patients who received allogeneic haematopoietic stem cell transplantation after myeloablative conditioning with or without antithymocyte globulin (ATG) due to acute leukaemia in 1st or 2nd complete remission. FOXP3 mRNA was measured by qPCR in purified CD4+ T cells from blood obtained before conditioning. Higher FOXP3 mRNA expression was associated with an increased relapse risk when conditioning included ATG (n = 43, hazard ratio [HR] 11.0 [2.50-48.4], p = 0.00001). No effect was observed in patients not receiving ATG (HR 0.95 [0.53-1.81]).
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Affiliation(s)
- Niels Jacobsen
- Department of HematologyRigshospitalet University HospitalCopenhagenDenmark
| | - Tina Frisch
- Department of Clinical ImmunologyTissue Typing LaboratoryRigshospitalet University HospitalCopenhagenDenmark
| | - Niels Keiding
- Department of BiostatisticsFaculty of Health SciencesCopenhagen UniversityCopenhagenDenmark
| | - Carsten Heilmann
- Paediatric and Adolescence MedicineRigshospitalet University HospitalCopenhagenDenmark
| | - Henrik Sengeløv
- Department of HematologyRigshospitalet University HospitalCopenhagenDenmark
| | - Hans O. Madsen
- Department of Clinical ImmunologyTissue Typing LaboratoryRigshospitalet University HospitalCopenhagenDenmark
| | - Ebbe Dickmeiss
- Department of Clinical ImmunologyTissue Typing LaboratoryRigshospitalet University HospitalCopenhagenDenmark
| | - Lars P. Ryder
- Department of Clinical ImmunologyTissue Typing LaboratoryRigshospitalet University HospitalCopenhagenDenmark
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16
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Gassen RB, Borges TJ, Pérez-Sáez MJ, Zhang H, Al Jurdi A, Llinàs-Mallol L, Aoyama B, Lima M, Pascual J, Sage PT, Murakami N, Riella LV. T cell depletion increases humoral response by favoring T follicular helper cells expansion. Am J Transplant 2022; 22:1766-1778. [PMID: 35320600 PMCID: PMC9262847 DOI: 10.1111/ajt.17038] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2022] [Revised: 02/27/2022] [Accepted: 03/19/2022] [Indexed: 01/25/2023]
Abstract
Antibody-mediated rejection is a major cause of long-term graft loss in kidney transplant patients. T follicular helper (Tfh) cells are crucial for assisting B cell differentiation and are required for an efficient antibody response. Anti-thymocyte globulin (ATG) is a widely used lymphocyte-depleting induction therapy. However, less is known about how ATG affects Tfh cell development and donor-specific antibody (DSA) formation. We observed an increase in circulating Tfh cells at 6 months after kidney transplant in patients who received ATG. Using an NP-OVA immunization model, we found that ATG-treated mice had a higher percentage of Tfh cells, germinal center B cells, and higher titers of antigen-specific antibodies compared to controls. ATG-treated animals had lower levels of IL-2, a known Bcl-6 repressor, but higher levels of IL-21, pSTAT3 and Bcl-6, favoring Tfh differentiation. In a mouse kidney transplant model, ATG-treated recipients showed an increase in Tfh cells, DSA and C4d staining in the allograft. Although ATG was effective in depleting T cells, it favored the expansion of Tfh cells following depletion. Concomitant use of IL-2, tacrolimus, or rapamycin with ATG was essential to control Tfh cell expansion. In summary, ATG depletion favors Tfh expansion, enhancing antibody-mediated response.
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Affiliation(s)
- Rodrigo Benedetti Gassen
- Center of Transplantation Science, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - Thiago J Borges
- Center of Transplantation Science, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | - María José Pérez-Sáez
- Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA.,Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Hengcheng Zhang
- Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Ayman Al Jurdi
- Center of Transplantation Science, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA
| | | | - Bruno Aoyama
- Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Maurício Lima
- Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Julio Pascual
- Department of Nephrology, Hospital del Mar, Barcelona, Spain
| | - Peter T Sage
- Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Naoka Murakami
- Renal Division, Brigham & Women’s Hospital, Harvard Medical School, Boston, MA, USA
| | - Leonardo V. Riella
- Center of Transplantation Science, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.,Department of Medicine, Division of Nephrology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, MA, USA
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17
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Sharma V, Kumar P, Kumar R, Chakraborty S, Namdeo M, Sazawal S, Kanga U, Seth T, Mitra DK. Interferon-gamma and perforin-positive T cells in acquired aplastic anemia: implication in therapeutic response. Clin Exp Immunol 2022; 207:272-278. [PMID: 35553631 PMCID: PMC9113177 DOI: 10.1093/cei/uxab006] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 09/24/2021] [Accepted: 12/09/2021] [Indexed: 11/12/2022] Open
Abstract
Acquired aplastic anemia (aAA) is an autoimmune disease, characterized by infiltration of T lymphocytes in the bone marrow with destruction of hematopoietic stem cells by the effector cells. Interferon-gamma (IFN-γ) and perforin are important mediators of cell destruction. In this flow cytometry-based study, we have investigated the percentage of intracellular IFN-γ+ and perforin+ CD5+ T cells in peripheral blood of newly diagnosed aAA patients before and after immunosuppressive therapy (IST). Patients were categorized as per standard disease severity and response to IST. The median percentage of IFN-γ+ and perforin+ CD5+ T cells was higher in untreated patients compared to healthy controls. The percentage of these cells was also increased in untreated severe and very severe aplastic anemia when compared with non-severe aplastic anemia patients. In patients before and after IST the median percentage of T cells producing IFN-γ and perforin was elevated in non-responders as compared to partial plus complete responders. The higher percentage of IFN-γ+ and perforin+ CD5+ T cells may be useful as an early diagnostic marker for aberrant activation of immune system and predict poor response to IST in aAA patients, who will benefit from alternative therapy.
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Affiliation(s)
- Vandana Sharma
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Prabin Kumar
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | | | - Sushmita Chakraborty
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Manju Namdeo
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Sudha Sazawal
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Uma Kanga
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
| | - Tulika Seth
- Department of Hematology, All India Institute of Medical Sciences, New Delhi, India
| | - Dipendra Kumar Mitra
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
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18
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Dziarmaga R, Ke D, Sapir-Pichhadze R, Cardinal H, Phan V, Piccirillo CA, Mazer B, Foster BJ. Age- and sex-mediated differences in T lymphocyte populations of kidney transplant recipients. Pediatr Transplant 2022; 26:e14150. [PMID: 34569133 DOI: 10.1111/petr.14150] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2021] [Revised: 09/10/2021] [Accepted: 09/13/2021] [Indexed: 11/29/2022]
Abstract
BACKGROUND Graft failure rates increase through childhood and adolescence, decline in adulthood, and are higher in female than male kidney transplant recipients (KTR) until middle age. We aimed to describe age- and sex-related differences in T-cell subsets among KTR to determine which differences may help to explain the differences in kidney graft failure rates. METHODS Effector T (Teff)-cell and regulatory T (Treg)-cell phenotypes in PBMCs from healthy controls and KTR, who were at least 1 year post-transplant with stable graft function under immunosuppression, were analyzed by flow cytometry. The effects of age, sex, and status (KTR or control) were analyzed using linear regressions. RESULTS We enrolled 20 male and 21 female KTR and 20 male and 20 female controls between 3 and 29 years of age. CD3+ T-cell frequencies were not associated with age or sex but were higher in KTR than controls. There were no differences in CD4+ and CD8+ frequencies. Th1 (IFNγ+ IL-4- IL-17A-) and Th17 (IL-17A+) frequencies within the CD4+ T-cell population were higher at older ages. The frequencies of FOXP3 + Helios + Treg cells in CD4+ CD25+ CD127- T cells were lower in females than males and in KTR than controls. CONCLUSIONS Increasing frequencies of Th1 and Th17 cells with increasing age mirrors the increasing graft failure rates from childhood to young adulthood. Importantly, sex differences in frequencies of circulating Treg cells may suggest a role in the sex differences in graft failure rates.
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Affiliation(s)
- Robert Dziarmaga
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada
| | - Danbing Ke
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada
| | - Ruth Sapir-Pichhadze
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Division of Nephrology and Multi-Organ Transplant Program, McGill University, Montreal, Quebec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada
| | - Héloïse Cardinal
- Département de Médecine, Université de Montréal, Montreal, Quebec, Canada.,Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada
| | - Véronique Phan
- Département de Pédiatrie, Université de Montréal, Montreal, Quebec, Canada.,Centre Hospitalier Universitaire Sainte-Justine, Montreal, Quebec, Canada
| | - Ciriaco A Piccirillo
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Department of Microbiology and Immunology, McGill University, Montreal, Quebec, Canada
| | - Bruce Mazer
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Division of Experimental Medicine, McGill University, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
| | - Bethany J Foster
- Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada.,Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, Quebec, Canada.,Department of Pediatrics, McGill University, Montreal, Quebec, Canada
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19
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Immunosuppression in the Age of Precision Medicine. Semin Nephrol 2022; 42:86-98. [DOI: 10.1016/j.semnephrol.2022.01.001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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20
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Ruhnke L, Stölzel F, Oelschlägel U, von Bonin M, Sockel K, Middeke JM, Röllig C, Jöhrens K, Schetelig J, Thiede C, Bornhäuser M. Long-Term Mixed Chimerism After Ex Vivo/In Vivo T Cell-Depleted Allogeneic Hematopoietic Cell Transplantation in Patients With Myeloid Neoplasms. Front Oncol 2021; 11:776946. [PMID: 34950586 PMCID: PMC8688843 DOI: 10.3389/fonc.2021.776946] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 11/08/2021] [Indexed: 01/06/2023] Open
Abstract
In patients who have undergone allogeneic hematopoietic cell transplantation (HCT), myeloid mixed donor chimerism (MC) is a risk factor for disease relapse. In contrast, several studies found favorable outcome in patients with lymphoid MC. Thus far, most studies evaluating MC focused on a short-term follow-up period. Here, we report the first case series of long-term survivors with MC. We screened 1,346 patients having undergone HCT for myeloid neoplasms at our center from 1996 to 2016; 443 patients with data on total peripheral blood mononuclear cells (PBMC)/CD4+/CD34+ short tandem repeat (STR) donor chimerism (DC) and follow-up ≥24 months post-HCT were included. We identified 10 patients with long-term MC (PBMC DC <95% at ≥12 months post-HCT). Median follow-up was 11 years. All patients had received combined ex vivo/in vivo T cell-depleted (TCD) peripheral blood stem cells; none experienced ≥grade 2 acute graft-versus-host disease (GVHD). The mean total PBMC, CD4+, and CD34+ DC of all patients were 95.88%, 85.84%, and 90.15%, respectively. Reduced-intensity conditioning (RIC) was associated with a trend to lower mean total DC. Of note, two patients who experienced relapse had lower CD34+ DC but higher CD4+ DC as compared with patients in continuous remission. Bone marrow evaluation revealed increased CD4+/FOXP3+ cells in patients with MC, which might indicate expansion of regulatory T cells (Tregs). Our results support known predictive factors associated with MC such as RIC and TCD, promote the value of CD34+ MC as a potential predictor of relapse, highlight the potential association of CD4+ MC with reduced risk of GVHD, and indicate a possible role of Tregs in the maintenance of immune tolerance post-HCT.
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Affiliation(s)
- Leo Ruhnke
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- *Correspondence: Leo Ruhnke,
| | - Friedrich Stölzel
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
| | - Uta Oelschlägel
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Malte von Bonin
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Katja Sockel
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Jan Moritz Middeke
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
| | - Christoph Röllig
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Korinna Jöhrens
- Institute of Pathology, University Hospital Dresden, TU Dresden, Dresden, Germany
| | - Johannes Schetelig
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- DKMS Clinical Trials Unit, Dresden, Germany
| | - Christian Thiede
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- AgenDix GmbH, Dresden, Germany
| | - Martin Bornhäuser
- Department of Internal Medicine I, University Hospital Dresden, TU Dresden, Dresden, Germany
- German Cancer Consortium (DKTK) partner site Dresden, Dresden, Germany
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany
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21
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Eguchi S, Uchida K, Takatsuki M, Okada S, Hidaka M, Soyama A, Hara T, Matsushima H, Adachi T, Nagai K, Watanabe M, Taketomi A, Okumura K, Yamashita K, Todo S. Anti-Donor Regulatory T-Cell Therapy in Adult-to-Adult Living Donor Liver Transplantation: A Case Report. Transplant Proc 2021; 53:2570-2575. [PMID: 34511248 DOI: 10.1016/j.transproceed.2021.08.026] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2021] [Accepted: 08/14/2021] [Indexed: 12/22/2022]
Abstract
We report on the case of a 50-year-old female patient with symptomatic polycystic liver disease who underwent living donor liver transplantation (LDLT) using right liver graft from her ABO-identical husband. To achieve operational tolerance, regulatory T-cell (T-reg)-based cell therapy was applied, following the protocol introduced by Todo et al. Briefly, donor lymphocytes were collected by leukapheresis 20 days before LDLT without any adverse events, and the cells were irradiated with a dose of 30 Gy and kept frozen. Lymphopheresis of the recipient was conducted in a similar manner 1 day before LDLT, and donor cells and recipient cells were cultured with anti-CD80/86 antibodies to induce the donor-specific T-reg. At 14 days of culture, the CD4+CD25+Foxp3+ cells had increased from 1.51% to 5.21%, and mixed lymphocyte reaction assay using an intracellular fluorescent dye carboxyfluorescein diacetate succinimidyl ester-labeling technique revealed donor-specific hyporesponsiveness of CD4-positive lymphocytes. On postoperative day (POD) 13 (14 days of culture), these cells were infused to the recipient intravenously without any adverse events. Initial immunosuppression consisted of tacrolimus, steroid and mycophenolate mofetil (MMF), and cyclophosphamide (40 mg/kg) administered on POD 5. Both the steroid and MMF were continued until 4 weeks after LDLT, and the patient was discharged on POD 30 with normal liver function. On POD 52, the patient developed acute cellular rejection and received appropriate reinforcement of immunosuppressive therapy and is currently doing well with normal liver function 30 months after LDLT with reduced anti-donor allo-activity. In summary, T-reg therapy was safely performed in adult LDLT, and we are following the patient carefully to determine whether she can achieve operational tolerance in the future.
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Affiliation(s)
- Susumu Eguchi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan.
| | - Koichiro Uchida
- Atopy (Allergy) Research Center, Juntendo University, Tokyo, Japan
| | - Mitsuhisa Takatsuki
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Satomi Okada
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Masaaki Hidaka
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Akihiko Soyama
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Takanobu Hara
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Hajime Matsushima
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Tomohiko Adachi
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences/Nagasaki University Hospital, Nagasaki, Japan
| | - Kazuhiro Nagai
- Department of Gastroenterological Surgery I, Hokkaido University, Hokkaido. Japan
| | - Masaaki Watanabe
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Akinobu Taketomi
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Ko Okumura
- Atopy (Allergy) Research Center, Juntendo University, Tokyo, Japan
| | - Kenichiro Yamashita
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, Japan
| | - Satoru Todo
- Research Institute, St. Mary's Hospital, Fokuoka, Japan
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22
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Rikhi R, Karnuta J, Hussain M, Collier P, Funchain P, Tang WHW, Chan TA, Moudgil R. Immune Checkpoint Inhibitors Mediated Lymphocytic and Giant Cell Myocarditis: Uncovering Etiological Mechanisms. Front Cardiovasc Med 2021; 8:721333. [PMID: 34434981 PMCID: PMC8381278 DOI: 10.3389/fcvm.2021.721333] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2021] [Accepted: 07/14/2021] [Indexed: 12/26/2022] Open
Abstract
The advent of immune checkpoint inhibitors (ICIs) has revolutionized the field of oncology, but these are associated with immune related adverse events. One such adverse event, is myocarditis, which has limited the continued immunosuppressive treatment options in patients afflicted by the disease. Pre-clinical and clinical data have found that specific ICI targets and precipitate distinct myocardial infiltrates, consistent with lymphocytic or giant cell myocarditis. Specifically, it has been reported that CTLA-4 inhibition preferentially results in giant cell myocarditis with a predominately CD4+ T cell infiltrate and PD-1 inhibition leads to lymphocytic myocarditis, with a predominately CD8+ T cell infiltrate. Our manuscript discusses the latest literature surrounding ICI pathways and targets, while detailing proposed mechanisms behind ICI mediated myocarditis.
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Affiliation(s)
- Rishi Rikhi
- Department of Medicine, Cleveland Clinic Foundation, Cleveland, OH, United States.,Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Jaret Karnuta
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States
| | - Muzna Hussain
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Patrick Collier
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.,Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Pauline Funchain
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.,Department of Hematology and Medical Oncology, Taussig Cancer Center Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Wai Hong Wilson Tang
- Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
| | - Timothy A Chan
- Center for Immunotherapy and Precision Immuno-Oncology, Lerner Research Institute, Cleveland, OH, United States
| | - Rohit Moudgil
- Department of Medicine, Case Western Reserve University, Cleveland, OH, United States.,Department of Cardiovascular Medicine, Heart, Vascular and Thoracic Institute, Cleveland Clinic Foundation, Cleveland, OH, United States
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23
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Jo S, Fang S. Therapeutic Strategies for Diabetes: Immune Modulation in Pancreatic β Cells. Front Endocrinol (Lausanne) 2021; 12:716692. [PMID: 34484126 PMCID: PMC8415970 DOI: 10.3389/fendo.2021.716692] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2021] [Accepted: 07/30/2021] [Indexed: 12/14/2022] Open
Abstract
Increased incidence of type I and type II diabetes has been prevailed worldwide. Though the pathogenesis of molecular mechanisms remains still unclear, there are solid evidence that disturbed immune homeostasis leads to pancreatic β cell failure. Currently, autoimmunity and uncontrolled inflammatory signaling pathways have been considered the major factors in the pathogenesis of diabetes. Many components of immune system have been reported to implicate pancreatic β cell failure, including helper T cells, cytotoxic T cells, regulatory T cells and gut microbiota. Immune modulation of those components using small molecules and antibodies, and fecal microbiota transplantation are undergoing in many clinical trials for the treatment of type I and type II diabetes. In this review we will discuss the basis of molecular pathogenesis focusing on the disturbed immune homeostasis in type I and type II diabetes, leading to pancreatic β cell destruction. Finally, we will introduce current therapeutic strategies and clinical trials by modulation of immune system for the treatment of type I and type II diabetes patients.
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Affiliation(s)
- Sugyeong Jo
- Department of Medical Science, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
| | - Sungsoon Fang
- Department of Medical Science, Brain Korea 21 Project for Medical Science, Yonsei University College of Medicine, Seoul, South Korea
- Severance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, South Korea
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24
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Schwarz A, Schäfer F, Framke T, Linnenweber-Held S, Richter N, Haller H. Risk Factors Influencing the Outcomes of Kidney Re-Transplantation. Ann Transplant 2021; 26:e928922. [PMID: 34267171 PMCID: PMC8290903 DOI: 10.12659/aot.928922] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND Our kidney transplant waitlist includes 20% re-transplantations (TX2). Knowing what to expect is a clinical obligation. MATERIAL AND METHODS We compared graft and patient survival of all 162 TX2 patients, transplanted 2000 to 2009, with 162 patients after first transplantation (TX1) matched for age, sex, living/non-living donation, and transplantation date. Patient follow-up was 10 years. RESULTS TX2 graft and patient survivals were inferior to TX1 (p<0.001 and p=0.047). TX2 patients had a longer cumulative dialysis vintage, more human leucocyte antigen (HLA) mismatches, more panel-reactive HLA antibodies, more often received induction therapy with rabbit-antithymocyte globulin (rATG), and had a lower body mass index (all p<0.05). Death from infection and graft failure by rejection was more frequent after TX2 (both p<0.05) but not after TX1. Multivariable Cox regression analysis revealed that both cohorts had graft failure and death risk associated with infection and cardiovascular disease, and graft failure by humoral rejection. However, only TX2 patients had an additional risk of graft failure with early inferior graft function and of patient death with ≥2 comorbidities. Moreover, Kaplan-Meier analysis showed that TX2 and not TX1 patients had a lower graft and patient survival associated with infection and with ≥2 comorbidities (all p<0.05). CONCLUSIONS Re-transplantation is associated with worse graft outcomes mainly because of immunologic and graft-quality reasons, although the high number of comorbidities and infection severities aside from cardiovascular disease drive mortality. The more frequent rATG induction of TX2 patients could promote infection by enhancing immunosuppression. By addressing comorbidities, outcomes could possibly be improved.
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Affiliation(s)
- Anke Schwarz
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Frank Schäfer
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
| | - Theodor Framke
- Institute for Biostatistics, Hannover Medical School, Hannover, Germany
| | | | - Nicolas Richter
- Department of Visceral Surgery and Transplantation, Hannover Medical School, Hannover, Germany
| | - Hermann Haller
- Department of Nephrology and Hypertension, Hannover Medical School, Hannover, Germany
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25
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Ritschl PV, Günther J, Hofhansel L, Ernst S, Ebner S, Sattler A, Weiß S, Weissenbacher A, Oberhuber R, Cardini B, Öllinger R, Biebl M, Denecke C, Margreiter C, Resch T, Schneeberger S, Maglione M, Kotsch K, Pratschke J. Perioperative Perfusion of Allografts with Anti-Human T-lymphocyte Globulin Does Not Improve Outcome Post Liver Transplantation-A Randomized Placebo-Controlled Trial. J Clin Med 2021; 10:jcm10132816. [PMID: 34202355 PMCID: PMC8267618 DOI: 10.3390/jcm10132816] [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: 03/28/2021] [Revised: 06/05/2021] [Accepted: 06/17/2021] [Indexed: 11/16/2022] Open
Abstract
Due to the lack of suitable organs transplant surgeons have to accept unfavorable extended criteria donor (ECD) organs. Recently, we demonstrated that the perfusion of kidney organs with anti-human T-lymphocyte globulin (ATLG) prior to transplantation ameliorates ischemia-reperfusion injury (IRI). Here, we report on the results of perioperative ATLG perfusion in a randomized, single-blinded, placebo-controlled, feasibility trial (RCT) involving 30 liver recipients (LTx). Organs were randomly assigned for perfusion with ATLG/Grafalon® (AP) (n = 16) or saline only (control perfusion = CP) (n = 14) prior to implantation. The primary endpoint was defined as graft function reflected by aspartate transaminase (AST) values at day 7 post-transplantation (post-tx). With respect to the primary endpoint, no significant differences in AST levels were shown in the intervention group at day 7 (AP: 53.0 ± 21.3 mg/dL, CP: 59.7 ± 59.2 mg/dL, p = 0.686). Similarly, exploratory analysis of secondary clinical outcomes (e.g., patient survival) and treatment-specific adverse events revealed no differences between the study groups. Among liver transplant recipients, pre-operative organ perfusion with ATLG did not improve short-term outcomes, compared to those who received placebo perfusion. However, ATLG perfusion of liver grafts was proven to be a safe procedure without the occurrence of relevant adverse events.
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Affiliation(s)
- Paul Viktor Ritschl
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
- Clinician Scientist Program, Berlin Institute of Health (BIH), Anna-Louisa-Karsch-Str. 2, 10178 Berlin, Germany
| | - Julia Günther
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Lena Hofhansel
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
- Department of Psychiatry, Psychotherapy and Psychosomatics, Faculty of Medicine, RWTH Aachen, 52074 Aachen, Germany
| | - Stefanie Ernst
- Biostatistics Unit, Clinical Research Unit, Berlin Institute of Health, Charité—Universitätsmedizin Berlin, 10117 Berlin, Germany;
| | - Susanne Ebner
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Arne Sattler
- Department of General, Visceral- and Vascular Surgery, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany;
| | - Sascha Weiß
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Annemarie Weissenbacher
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Rupert Oberhuber
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Benno Cardini
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Robert Öllinger
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Matthias Biebl
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Christian Denecke
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
| | - Christian Margreiter
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Thomas Resch
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Stefan Schneeberger
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Manuel Maglione
- Center for Operative Medicine, Department of Visceral, Transplant and Thoracic Surgery, Medical University of Innsbruck, 5020 Innsbruck, Austria; (J.G.); (L.H.); (S.E.); (A.W.); (R.O.); (B.C.); (C.M.); (T.R.); (S.S.); (M.M.)
| | - Katja Kotsch
- Department of General, Visceral- and Vascular Surgery, Campus Benjamin Franklin, Charité—Universitätsmedizin Berlin, 12203 Berlin, Germany;
- Correspondence: ; Tel.: +49-30-450-552247
| | - Johann Pratschke
- Department of Surgery, Campus Charité-Mitte and Campus Virchow-Klinikum, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany; (P.V.R.); (S.W.); (R.Ö.); (M.B.); (C.D.); (J.P.)
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26
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Shaw BI, Schmitz R, Flores WJ, Magnani DM, Li J, Song M, Kirk AD. A comparative study of human-and rhesus-specific antithymocyte globulins in Rhesus macaques. Clin Transplant 2021; 35:e14369. [PMID: 34021521 DOI: 10.1111/ctr.14369] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2021] [Revised: 05/10/2021] [Accepted: 05/17/2021] [Indexed: 11/28/2022]
Abstract
Rabbit antithymocyte globulin (RATG) preparations are widely used in transplantation. They are developed in vivo against thymocytes and contain polyclonal antibodies specific for myriad cellular targets. The rhesus monkey is commonly used as a preclinical transplant model, but the fidelity of commercially available human-specific RATGs to anticipate the effects of RATGs in rhesus has not been established. We therefore developed two rhesus-specific ATGs (rhATG) and compared them to human-specific RATG (huATG, Thymoglobulin® ) in rhesus monkeys, assessing the magnitude and phenotype of depletion peripherally and in lymph nodes. Four primates were assigned to each group and received 20 mg/kg of drug. Depletion, repopulation, and changes in lymphocyte subsets were evaluated in peripheral blood and lymph nodes by flow cytometry over four months. We observed similar qualitative changes in lymphocyte subsets, but a generally more profound depletion with huATG compared to either rhATG. Peripheral homeostatic proliferation rather than thymic output was the major mechanism for repopulation with all RATGs. Repopulation was slower but qualitatively similar when examining RATGs in additional animals receiving concomitant chronic immunosuppression. Depletional induction is similar to human- and rhesus-specific RATGs in rhesus macaques. Both rhesus- and human-specific agents appear appropriate for preclinical modeling of clinical RATG use.
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Affiliation(s)
- Brian I Shaw
- Department of Surgery, Duke University, Durham, NC, USA
| | - Robin Schmitz
- Department of Surgery, Duke University, Durham, NC, USA
| | - Walter J Flores
- MassBiologics, University of Massachusetts Medical School, Boston, MA, USA
| | - Diogo M Magnani
- MassBiologics, University of Massachusetts Medical School, Boston, MA, USA
| | - Jie Li
- Department of Surgery, Duke University, Durham, NC, USA
| | - Mingqing Song
- Department of Surgery, Duke University, Durham, NC, USA
| | - Allan D Kirk
- Department of Surgery, Duke University, Durham, NC, USA
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27
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Successful Treatment of Steroid-Refractory Checkpoint Inhibitor Myocarditis with Globulin Derived-Therapy: A case report and literature review. Am J Med Sci 2021; 362:424-432. [PMID: 33974854 DOI: 10.1016/j.amjms.2021.04.018] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 01/15/2021] [Accepted: 04/28/2021] [Indexed: 01/22/2023]
Abstract
Immune checkpoint inhibitor (ICI) monoclonal antibody drugs are an important interface of immunology and cancer biology with the intended goal to create cancer specific treatments with less systemic toxicity. Recognition of immune-related adverse events is critical and these include significant cardiovascular toxicity and myocarditis. Compared with other immune-related events, ICI associated myocarditis is rare but is associated with high mortality. The majority of cases present early in the course of therapy and patients can rapidly progress to fulminant myocarditis. Initially, the mainstay of treatment in patients with ICI-associated myocarditis is immunosuppressive therapy with glucocorticoids. For those who do not respond to steroids, the optimal treatment is unclear. This review summarizes the potential adjunctive treatment options for patients with steroid-refractory myocarditis by illustrating a case of myocarditis that was treated with Thymoglobulin and immunoglobulin.
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28
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Dou L, Wang L, Li X, Liu Y, Li F, Wang L, Gao X, Huang W, Wang S, Gao C, Yu L, Liu D. Role of antithymocyte globulin in matched sibling donor peripheral blood stem cell transplantation for hematologic malignancies. Medicine (Baltimore) 2021; 100:e24725. [PMID: 33663084 PMCID: PMC7909208 DOI: 10.1097/md.0000000000024725] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2020] [Accepted: 01/19/2021] [Indexed: 01/05/2023] Open
Abstract
BACKGROUND High incidence of chronic graft-versus-host disease (GVHD) has been a major drawback of matched sibling donor peripheral blood stem cell transplantation (MSD -PBSCT). This study aimed to investigate the safety and efficacy of antithymocyte globulin (ATG) as a standardized part of GVHD prophylaxis in patients receiving MSD -PBSCT. METHODS A total of 72 patients with hematological malignancies receiving MSD -PBSCT who displayed similar baseline characteristics were either given rabbit ATG ( n = 42) or no ATG (n = 30), in addition to cyclosporine, methotrexate, and mycophenolate mofetil as a standard GVHD prophylaxis regimen. Either patients or donors aged ≥40 years were included in the study. Thymoglobulin was administered at a daily dose of 1.5 mg/kg on day -5 and 3.5 mg/kg on day -4 prior to transplant (the total dose was 5 mg/kg). RESULTS After a median follow-up of 874 days, the 3-year cumulative incidence of chronic GVHD (cGVHD) was 37.3% in the ATG group and 52.1% in the non -ATG group. The 3-year overall and disease-free survival probability were 71.0% and 62.0% (ATG versus non -ATG, P = .262) and 66.7% and 58.4% (ATG versus non -ATG, P = .334). No difference was found in the 2-year cumulative incidence of nonrelapse mortality and relapse between the ATG and non -ATG groups. This significant reduction in the incidence of cGVHD without increased relapse risk and nonrelapse mortality led to a 3-year GVHD-free, relapse-free survival probability of 66.7% and 40.0% in the ATG and non-ATG groups, respectively. CONCLUSIONS These data suggested that rabbit antithymocyte globulin in the current protocol for GVHD prophylaxis was well tolerable and efficacious.The clinical trial was registered on January 1, 2016 (ClinicalTrials.gov Identifier NCT02677181). https://clinicaltrials.gov/ct2/show/NCT02677181.
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Affiliation(s)
| | | | - Xin Li
- Department of Quality Control, Chinese PLA General Hospital, Beijing, China
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29
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A Clinical Trial With Adoptive Transfer of Ex Vivo-induced, Donor-specific Immune-regulatory Cells in Kidney Transplantation-A Second Report. Transplantation 2021; 104:2415-2423. [PMID: 33125206 DOI: 10.1097/tp.0000000000003149] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND Although the outcome of kidney transplantation (KTx) has improved, various adverse effects of immunosuppressants and chronic rejection aggravate the long-term prognosis of patients. Therefore, the induction of immune tolerance may be an effective therapeutic strategy. METHODS A clinical trial aiming at immune tolerance induction was conducted in kidney transplant recipients from HLA mismatched living donors by infusing autologous donor-specific regulatory T cells (Treg). To obtain Treg, recipient's peripheral blood mononuclear cells were cocultured with irradiated donor cells in the presence of anti-CD80/CD86 monoclonal antibody for 2 weeks. For preconditioning, splenectomy + cyclophosphamide (CP) was employed in the first series (group A; n = 9). In group B, splenectomy was substituted by preadministration of rituximab (group B; n = 3). In the latest cases, rituximab + rabbit antithymocyte globulin was administered instead of cyclophosphamide (group C; n = 4). Twelve days after KTx, the cultured cells were intravenously infused, and immunosuppressants were gradually tapered thereafter. RESULTS Although mixed lymphocyte reaction was remarkably suppressed in a donor-specific fashion, 6 out of 9 patients from group A, 1 out of 3 from group B, and 1 out of 4 from group C developed acute rejection within 1 year after KTx. Complete cessation of immunosuppression was not achieved, and a small dose of immunosuppressants was continued. CONCLUSIONS The adoptive transfer of autologous ex vivo-expanded Treg is 1 of the options to possibly induce alloimmune hyporesponsiveness. However, in the present study, further regimen optimization is still required and should be the focus of future investigations.
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30
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Nobakht E, Jagadeesan M, Paul R, Bromberg J, Dadgar S. Precision Medicine in Kidney Transplantation: Just Hype or a Realistic Hope? Transplant Direct 2021; 7:e650. [PMID: 33437865 PMCID: PMC7793397 DOI: 10.1097/txd.0000000000001102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/27/2020] [Accepted: 10/29/2020] [Indexed: 12/17/2022] Open
Abstract
Desirable outcomes including rejection- and infection-free kidney transplantation are not guaranteed despite current strategies for immunosuppression and using prophylactic antimicrobial medications. Graft survival depends on factors beyond human leukocyte antigen matching such as the level of immunosuppression, infections, and management of other comorbidities. Risk stratification of transplant patients based on predisposing genetic modifiers and applying precision pharmacotherapy may help improving the transplant outcomes. Unlike certain fields such as oncology in which consistent attempts are being carried out to move away from the "error and trial approach," transplant medicine is lagging behind in implementing personalized immunosuppressive therapy. The need for maintaining a precarious balance between underimmunosuppression and overimmunosuppression coupled with adverse effects of medications calls for a gene-based guidance for precision pharmacotherapy in transplantation. Technologic advances in molecular genetics have led to increased accessibility of genetic tests at a reduced cost and have set the stage for widespread use of gene-based therapies in clinical care. Evidence-based guidelines available for precision pharmacotherapy have been proposed, including guidelines from Clinical Pharmacogenetics Implementation Consortium, the Pharmacogenomics Knowledge Base National Institute of General Medical Sciences of the National Institutes of Health, and the US Food and Drug Administration. In this review, we discuss the implications of pharmacogenetics and potential role for genetic variants-based risk stratification in kidney transplantation. A single score that provides overall genetic risk, a polygenic risk score, can be achieved by combining of allograft rejection/loss-associated variants carried by an individual and integrated into practice after clinical validation.
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Affiliation(s)
- Ehsan Nobakht
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Muralidharan Jagadeesan
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Rohan Paul
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
| | - Jonathan Bromberg
- Department of Surgery, University of Maryland School of Medicine, Baltimore, MD
| | - Sherry Dadgar
- Division of Renal Diseases and Hypertension, Department of Medicine, George Washington University School of Medicine, Washington, DC
- Personalized Medicine Care Diagnostics Laboratory (PMCDx), Inc., Germantown, MD
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31
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Yu J, Liu Z, Li C, Wei Q, Zheng S, Saeb-Parsy K, Xu X. Regulatory T Cell Therapy Following Liver Transplantation. Liver Transpl 2021; 27:264-280. [PMID: 37160016 DOI: 10.1002/lt.25948] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/07/2020] [Revised: 10/25/2020] [Accepted: 10/31/2020] [Indexed: 12/17/2022]
Abstract
Liver transplantation (LT) is considered the gold standard of curative treatment for patients with end-stage liver disease or nonresectable hepatic malignant tumors. Rejection after LT is the main nontechnical factor affecting the prognosis of recipients. Medical and surgical advances, combined with improved immunosuppression with drugs such as calcineurin inhibitors (CNIs), have contributed to an increase in 1-year graft survival to around 80%. However, medium- and long-term improvements in LT outcomes have lagged behind. Importantly, CNIs and other classical immunosuppressive drugs are associated with significant adverse effects, including malignancies, cardiovascular disease, and severe renal dysfunction. Immunomodulation using regulatory T cells (Tregs) is emerging as a promising alternative to classical immunosuppression. Since their discovery, the immunomodulatory effects of Tregs have been demonstrated in a range of diseases. This has rejuvenated the interest in using Tregs as a therapeutic strategy to induce immune tolerance after LT. In this review, we first summarize the discovery and development of Tregs. We then review the preclinical data supporting their production, mechanism of action, and therapeutic efficacy followed by a summary of relevant clinical trials. Finally, we discuss the outstanding challenges of Treg therapy and its future prospects for routine use in LT.
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Affiliation(s)
- Jiongjie Yu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Zhikun Liu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Changbiao Li
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
| | - Shusen Zheng
- Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China.,Department of Hepatobiliary and Pancreatic Surgery, Shulan (Hangzhou) Hospital, Hangzhou, China
| | - Kourosh Saeb-Parsy
- Department of Surgery, University of Cambridge, Cambridge, UK.,Cambridge National Institute of Health Research Biomedical Research Centre, Cambridge, UK
| | - Xiao Xu
- Department of Hepatobiliary and Pancreatic Surgery, Affiliated Hangzhou First People's Hospital, Zhejiang University School of Medicine, Hangzhou, China.,Division of Hepatobiliary and Pancreatic Surgery, Department of Surgery, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.,National Health and Family Planning Commission (NHFPC) Key Laboratory of Combined Multi-Organ Transplantation, Hangzhou, China
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32
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Mashima K, Oh I, Fujiwara K, Izawa J, Takayama N, Nakano H, Kawasaki Y, Minakata D, Yamasaki R, Morita K, Ashizawa M, Yamamoto C, Hatano K, Sato K, Ohmine K, Fujiwara SI, Ohno N, Kanda Y. Comparison of alemtuzumab, anti-thymocyte globulin, and post-transplant cyclophosphamide for graft-versus-host disease and graft-versus-leukemia in murine models. PLoS One 2021; 16:e0245232. [PMID: 33428661 PMCID: PMC7799789 DOI: 10.1371/journal.pone.0245232] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2020] [Accepted: 12/24/2020] [Indexed: 12/22/2022] Open
Abstract
Graft-versus-host disease is a major complication after allogeneic hematopoietic stem cell transplantation for hematological malignancies. Immunosuppressive drugs, such as anti-thymocyte globulin, alemtuzumab, and post-transplant cyclophosphamide, have been used to prevent graft-versus-host disease in HLA-mismatched haploidentical hematopoietic stem cell transplantation. Here, we investigated whether these drugs could ameliorate graft-versus-host disease without diminishing the graft-versus-leukemia effect by using a xenogeneic transplanted graft-versus-host disease/graft-versus-leukemia model. Anti-thymocyte globulin treatment diminished graft-versus-host disease symptoms, completely depleted the infiltration of inflammatory cells in the liver and intestine, and led to prolonged survival. By contrast, improvement after post-transplant cyclophosphamide treatment remained minimal. Alemtuzumab treatment modestly prolonged survival despite an apparent decrease of Tregs. In the graft-versus-leukemia model, 1.5 to 2.0 mg/kg of anti-thymocyte globulin and 0.6 to 0.9 mg/kg of alemtuzumab reduced graft-versus-host disease with minimal loss of graft-versus-leukemia effect. Mice treated with 400 mg/kg of post-transplant cyclophosphamide did not develop graft-versus-host disease or leukemia, but it was difficult to evaluate the graft-versus-leukemia effect due to the sensitivity of A20 cells to cyclophosphamide. Although the current settings provide narrow optimal therapeutic windows, further studies are warranted to maximize the benefits of each immunosuppressant.
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Affiliation(s)
- Kiyomi Mashima
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Iekuni Oh
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Ken Fujiwara
- Division of Histology and Cell Biology, Department of Anatomy, School of Medicine, Jichi Medical University, Tochigi, Japan
| | - Junko Izawa
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Norihito Takayama
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Hirofumi Nakano
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Yasufumi Kawasaki
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Daisuke Minakata
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Ryoko Yamasaki
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kaoru Morita
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Masahiro Ashizawa
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Chihiro Yamamoto
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kaoru Hatano
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Kazuya Sato
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Ken Ohmine
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Shin-Ichiro Fujiwara
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
| | - Nobuhiko Ohno
- Division of Histology and Cell Biology, Department of Anatomy, School of Medicine, Jichi Medical University, Tochigi, Japan
| | - Yoshinobu Kanda
- Division of Hematology, Department of Medicine, Jichi Medical University, Tochigi, Japan
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33
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Kröger N. Preventing Graft-Versus-Host Disease Without Losing Graft-Versus-Leukemia Effect After Allogeneic Stem-Cell Transplantation. J Clin Oncol 2020; 38:3357-3360. [PMID: 32706637 DOI: 10.1200/jco.20.01756] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Nicolaus Kröger
- Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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34
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Emoto S, Shibasaki S, Nagatsu A, Goto R, Ono H, Fukasaku Y, Igarashi R, Ota T, Fukai M, Shimamura T, Saiga K, Taketomi A, Murakami M, Todo S, Yamashita K. Triazolopyrimidine derivative NK026680 and donor-specific transfusion induces CD4 +CD25 +Foxp3 + T cells and ameliorates allograft rejection in an antigen-specific manner. Transpl Immunol 2020; 65:101338. [PMID: 33022372 DOI: 10.1016/j.trim.2020.101338] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2020] [Revised: 10/02/2020] [Accepted: 10/02/2020] [Indexed: 11/19/2022]
Abstract
We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST). BALB/c (H-2d) heart graft were transplanted into C57BL/6 (H-2b) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2k). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8+ T cells in the spleen and inhibited infiltration of CD8+ T cells into the graft. Depletion of CD25+ cells inhibited the graft prolonging effect of the NK026680 plus DST treatment. NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs.
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Affiliation(s)
- Shin Emoto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Susumu Shibasaki
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Akihisa Nagatsu
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Ryoichi Goto
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Hitoshi Ono
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Yasutomo Fukasaku
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Rumi Igarashi
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Takuji Ota
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Moto Fukai
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Tsuyoshi Shimamura
- Division of Organ Transplantation, Hokkaido University Hospital, Sapporo, Japan.
| | - Kan Saiga
- Pharmaceutical Research Laboratories, Nippon Kayaku Co., Ltd., Tokyo, Japan.
| | - Akinobu Taketomi
- Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
| | - Masaaki Murakami
- Division of Molecular Psychoimmunology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
| | - Satoru Todo
- Research Institute of St. Mary's Hospital, Kurume, Japan.
| | - Kenichiro Yamashita
- Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
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35
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Comparative efficacy of 20 graft-versus-host disease prophylaxis therapies for patients after hematopoietic stem-cell transplantation: A multiple-treatments network meta-analysis. Crit Rev Oncol Hematol 2020; 150:102944. [DOI: 10.1016/j.critrevonc.2020.102944] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Revised: 01/08/2020] [Accepted: 03/19/2020] [Indexed: 12/12/2022] Open
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36
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Sergeant E, Buysse M, Devos T, Sprangers B. Multipotent mesenchymal stromal cells in kidney transplant recipients: The next big thing? Blood Rev 2020; 45:100718. [PMID: 32507576 DOI: 10.1016/j.blre.2020.100718] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2019] [Revised: 04/13/2020] [Accepted: 05/11/2020] [Indexed: 12/20/2022]
Abstract
Bone marrow-derived multipotent mesenchymal stromal cells (BM-MSCs) are non-haematopoietic cells present in the bone marrow stroma. They have the potential to modulate immune responses and exhibit a capacity to promote immune tolerance. Although the efficacy of immunosuppressive drugs has improved significantly, thereby ameliorating renal graft outcome, the use of these drugs still carries an increased risk of malignancies and opportunistic infections, and sometimes fail to prevent chronic allograft rejection or recurrence of the original kidney disease. As such, there is strong interest in ways to induce immune tolerance and thereby tempering or avoiding conventional immunosuppressive drugs. Cellular immunomodulation by MSCs can create a new way to induce transplant tolerance. This review will give a critical overview of the use of BM-MSCs as a cell-based immunosuppressive therapy in kidney transplant recipients. In vitro studies revealed several mechanisms that can clarify the immunomodulatory potential of BM-MSCs. Several clinical studies showed that BM-MSCs can modulate T-cell proliferation and can alter the ratio of T-cell subsets, favoring immune tolerance. However, this immunomodulation was often not associated with better clinical outcome during follow-up when compared to control groups. Some clinical studies found that BM-MSCs allow a reduction in dose of conventional immunosuppressive drugs and prevent acute graft dysfunction. Most clinical studies emphasized that BM-MSC infusion was safe. This review suggests that the use of BM-MSCs as cell-based immunosuppression therapy in kidney transplant recipients has potential, however some caution regarding their clinical use is appropriate. Mechanisms by which BM-MSCs induce transplant tolerance and factors that can alter their functionality need to be analyzed in more detail before clinical use.
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Affiliation(s)
- Elien Sergeant
- Division of Internal Medicine, University Hospitals Leuven, Leuven, Belgium.
| | - Malicorne Buysse
- Division of Hematology, University Hospitals Ghent, Ghent, Belgium.
| | - Timothy Devos
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Hematology, University Hospitals Leuven, Leuven, Belgium.
| | - Ben Sprangers
- Department of Microbiology and Immunology, Laboratory of Molecular Immunology (Rega Institute), KU Leuven, Leuven, Belgium; Division of Nephrology, University Hospitals Leuven, Leuven, Belgium.
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de Wolf ACMT, Herberts CA, Hoefnagel MHN. Dawn of Monitoring Regulatory T Cells in (Pre-)clinical Studies: Their Relevance Is Slowly Recognised. Front Med (Lausanne) 2020; 7:91. [PMID: 32300597 PMCID: PMC7142310 DOI: 10.3389/fmed.2020.00091] [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: 11/19/2019] [Accepted: 03/03/2020] [Indexed: 12/14/2022] Open
Abstract
Regulatory T cells (Tregs) have a prominent role in the control of immune homeostasis. Pharmacological impact on their activity or balance with effector T cells could contribute to (impaired) clinical responses or adverse events. Monitoring treatment-related effects on T cell subsets may therefore be part of (pre-)clinical studies for medicinal products. However, the extent of immune monitoring performed in studies for marketing authorisation and the degree of correspondence with data available in the public domain is not known. We evaluated the presence of T cell immunomonitoring in 46 registration dossiers of monoclonal antibodies indicated for immune-related disorders and published scientific papers. We found that the depth of Treg analysis in registration dossiers was rather small. Nevertheless, data on treatment-related Treg effects are available in public academia-driven studies (post-registration) and suggest that Tregs may act as a biomarker for clinical responses. However, public data are fragmented and obtained with heterogeneity of experimental approaches from a diversity of species and tissues. To reveal the potential added value of T cell (and particular Treg) evaluation in (pre-)clinical studies, more cell-specific data should be acquired, at least for medicinal products with an immunomodulatory mechanism. Therefore, extensive analysis of T cell subset contribution to clinical responses and the relevance of treatment-induced changes in their levels is needed. Preferably, industry and academia should work together to obtain these data in a standardised manner and to enrich our knowledge about T cell activity in disease pathogenesis and therapies. This will ultimately elucidate the necessity of T cell subset monitoring in the therapeutic benefit-risk assessment.
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Sim JH, Han SS, Lee DS, Kim YS, Lee H, Kim HR. Analysis of Immune Cell Repopulation After Anti-thymocyte Globulin Administration for Steroid-Resistant T-cell–mediated Rejection. Transplant Proc 2020; 52:759-766. [DOI: 10.1016/j.transproceed.2020.01.013] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2019] [Revised: 01/03/2020] [Accepted: 01/22/2020] [Indexed: 01/05/2023]
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Association of More Intensive Induction With Less Acute Rejection Following Intestinal Transplantation: Results of 445 Consecutive Cases From a Single Center. Transplantation 2020; 104:2166-2178. [PMID: 31929425 DOI: 10.1097/tp.0000000000003074] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
BACKGROUND In intestinal transplantation, acute cellular rejection (ACR) remains a significant challenge to achieving long-term graft survival. It is still not clear which are the most important prognostic factors. METHODS We performed a Cox multivariable analysis of the hazard rates of developing any ACR, severe ACR, and cause-specific graft loss during the first 60 months posttransplant among 445 consecutive intestinal transplant recipients at our institution since 1994. Of particular interest was to determine the prognostic influence of induction type: rabbit antithymocyte globulin (rATG; 2 mg/kg × 5)/rituximab (150 mg/m × 1; begun in 2013), alemtuzumab (2001-2011), and less intensive forms. RESULTS First ACR and severe ACR occurred in 61.3% (273/445) and 22.2% (99/445) of cases. The following 3 multivariable predictors were associated with significantly lower hazard rates of developing ACR and severe ACR: transplant type modified multivisceral or full multivisceral (P = 0.0009 and P < 0.000001), rATG/rituximab induction (P < 0.000001 and P < 0.01), and alemtuzumab induction (P = 0.004 and P = 0.07). For both ACR and severe ACR, the protective effects of rATG/rituximab and alemtuzumab were highly significant (P ≤ 0.000005 for ACR; P ≤ 0.01 for severe ACR) but only during the first 24 days posttransplant (when the ACR hazard rate was at its peak). The prognostic effects of rATG/rituximab and alemtuzumab on ACR/severe ACR disappeared beyond 24 days posttransplant (ie, nonproportional hazards). While significant protective effects of both rATG/rituximab and alemtuzumab existed during the first 6 months posttransplant for the hazard rate of graft loss-due-to-rejection (P = 0.01 and P = 0.003), rATG/rituximab was additionally associated with a consistently lower hazard rate of graft loss-due-to-infection (P = 0.003). All significant effects remained after controlling for the propensity-to-be-transplanted since 2013. CONCLUSIONS More intensive induction was associated with a significant lowering of ACR risk, particularly during the early posttransplant period.
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Podestà MA, Binder C, Sellberg F, DeWolf S, Shonts B, Ho SH, Obradovic A, Waffarn E, Danzl N, Berglund D, Sykes M. Siplizumab selectively depletes effector memory T cells and promotes a relative expansion of alloreactive regulatory T cells in vitro. Am J Transplant 2020; 20:88-100. [PMID: 31319439 PMCID: PMC6940533 DOI: 10.1111/ajt.15533] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2018] [Revised: 07/02/2019] [Accepted: 07/10/2019] [Indexed: 01/25/2023]
Abstract
Siplizumab, a humanized anti-CD2 monoclonal antibody, has been used in conditioning regimens for hematopoietic cell transplantation and tolerance induction with combined kidney-bone marrow transplantation. Siplizumab-based tolerance induction regimens deplete T cells globally while enriching regulatory T cells (Tregs) early posttransplantation. Siplizumab inhibits allogeneic mixed-lymphocyte reactions (MLRs) in vitro. We compared the impact of siplizumab on Tregs versus other T cell subsets in HLA-mismatched allogeneic MLRs using PBMCs. Siplizumab predominantly reduced the percentage of CD4+ and CD8+ effector memory T cells, which express higher CD2 levels than naïve T cells or resting Tregs. Conversely, siplizumab enriched proliferating CD45RA- FoxP3HI cells in MLRs. FoxP3 expression was stable over time in siplizumab-containing cultures, consistent with enrichment for bona fide Tregs. Consistently, high-throughput TCRβ CDR3 sequencing of sorted unstimulated and proliferating T cells in MLRs revealed selective expansion of donor-reactive Tregs along with depletion of donor-reactive CD4+ effector/memory T cells in siplizumab-containing MLRs. These results indicate that siplizumab may have immunomodulatory functions that may contribute to its success in tolerance-inducing regimens. Our studies also confirm that naïve in addition to effector/memory T cells contribute to the allogeneic MLR and mandate further investigation of the impact of siplizumab on alloreactive naïve T cells.
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Affiliation(s)
- Manuel Alfredo Podestà
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA.,Current affiliations: Università degli Studi di Milano, Milan, Italy and Istituto di Ricerche Farmacologiche Mario Negri IRCCS, Bergamo, Italy
| | - Christian Binder
- ITB-Med AB, Sonja Kovalevskys gata 4, 113 66 Stockholm, Sweden,Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden
| | - Felix Sellberg
- ITB-Med AB, Sonja Kovalevskys gata 4, 113 66 Stockholm, Sweden,Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden
| | - Susan DeWolf
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - Brittany Shonts
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - Siu-Hong Ho
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - Aleksandar Obradovic
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - Elizabeth Waffarn
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - Nichole Danzl
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA
| | - David Berglund
- ITB-Med AB, Sonja Kovalevskys gata 4, 113 66 Stockholm, Sweden,Department of Immunology, Genetics and Pathology, Section of Clinical Immunology, Uppsala University, Uppsala, Sweden
| | - Megan Sykes
- Columbia Center for Translational Immunology, Department of Medicine, Columbia University Medical Center, NY, USA.,Department of Microbiology & Immunology, Columbia University Medical Center, NY, USA and Department of Surgery, Columbia University Medical Center, NY, USA
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Suk Lee Y, Davila E, Zhang T, Milmoe HP, Vogel SN, Bromberg JS, Scalea JR. Myeloid-derived suppressor cells are bound and inhibited by anti-thymocyte globulin. Innate Immun 2019; 25:46-59. [PMID: 30782043 PMCID: PMC6830891 DOI: 10.1177/1753425918820427] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
Myeloid-derived suppressor cells (MDSCs) inhibit T cell responses and are
relevant to cancer, autoimmunity and transplant biology. Anti-thymocyte globulin
(ATG) is a commonly used T cell depletion agent, yet the effect of ATG on MDSCs
has not been investigated. MDSCs were generated in Lewis Lung Carcinoma 1
tumor-bearing mice. MDSC development and function were assessed in
vivo and in vitro with and without ATG
administration. T cell suppression assays, RT-PCR, flow cytometry and arginase
activity assays were used to assess MDSC phenotype and function. MDSCs increased
dramatically in tumor-bearing mice and the majority of splenic MDSCs were of the
polymorphonuclear subset. MDSCs potently suppressed T cell proliferation.
ATG-treated mice developed 50% fewer MDSCs and these MDSCs were significantly
less suppressive of T cell proliferation. In vitro, ATG
directly bound 99.6% of MDSCs. CCR7, L-selectin and LFA-1 were expressed by both
T cells and MDSCs, and binding of LFA-1 was inhibited by ATG pre-treatment.
Arg-1 and PD-L1 transcript expression were reduced 30–40% and arginase activity
decreased in ATG-pretreated MDSCs. MDSCs were bound and functionally inhibited
by ATG. T cells and MDSCs expressed common Ags which were also targets of ATG.
ATG may be helpful in tumor models seeking to suppress MDSCs. Alternatively, ATG
may inadvertently inhibit important T cell regulatory events in autoimmunity and
transplantation.
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Affiliation(s)
- Young Suk Lee
- 1 Department of Surgery, University of Maryland, Baltimore, USA
| | - Eduardo Davila
- 2 Department of Microbiology and Immunology, University of Maryland, Baltimore, USA
| | - Tianshu Zhang
- 1 Department of Surgery, University of Maryland, Baltimore, USA
| | - Hugh P Milmoe
- 1 Department of Surgery, University of Maryland, Baltimore, USA
| | - Stefanie N Vogel
- 2 Department of Microbiology and Immunology, University of Maryland, Baltimore, USA
| | - Jonathan S Bromberg
- 1 Department of Surgery, University of Maryland, Baltimore, USA.,2 Department of Microbiology and Immunology, University of Maryland, Baltimore, USA
| | - Joseph R Scalea
- 1 Department of Surgery, University of Maryland, Baltimore, USA.,2 Department of Microbiology and Immunology, University of Maryland, Baltimore, USA
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Xavier P, Magalhães M, Sampaio-Norton S, Guimarães T, Oliveira JG. Differences for T-Cell Subtypes in Aspiration Biopsies of Patients With Kidney Transplant Under Polyclonal and Monoclonal Immunosuppressive Treatments. Transplant Proc 2019; 51:3271-3274. [PMID: 31732211 DOI: 10.1016/j.transproceed.2019.07.031] [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: 01/08/2019] [Revised: 06/05/2019] [Accepted: 07/09/2019] [Indexed: 11/20/2022]
Abstract
Thymoglobulin, or antithymocyte globulin (ATG), and anti-interleukin 2α (IL-2α) chain receptor antibody (IL-2αRAb) achieve comparable good results in kidney transplantation notwithstanding different actions on immune cells. Previously, we reported the usefulness of flow cytometry (FC) analysis of lymphocyte subsets present in peripheral blood sample (PBL) and fine-needle aspiration biopsies (FNABs) for clinical surveillance, as, FC reaches very high predictive positive values for acute rejection diagnosis. Now we report an FC study on 2 kidney transplantation (KT) groups under ATG (n = 19) and IL-2αRAb (n = 24) treatment. Both groups were further treated with calcineurin inhibitors mycophenolate mofetil (MMF) and prednisone. PBL and FNAB samples were collected on day 7 post-KT, stained for several T- and B-lymphocyte subsets, and acquired using FACScan. Statistical analysis were done by Mann-Whitney U test. FNAB results showed a significant downregulation by ATG of CD3 (P < .001), CD4 (P = .009), CD4CD29 (P = .003), and CD2 (P ≤ .001) and significant upregulation of death receptor (DR) (P = .03), CD3CD69 (P < .001), and CD3CD25 (P < .0001) as compared to groups treated with IL-2αRAb. For PBL, the same trend was seen for CD3, CD4, CD2, CD3CD25, CD3CD69, CD4CD29, and DR plus a downregulation of CD45RO (P = .001) and an upregulation of CD4CD45RA (P < .0001) in IL-2αRAb. This study shows that among stable KTs, ATG as compared to IL-2αRAb induces a significant downregulation of a subset of T-memory (CD4CD29) cells but an upregulation of antigen-experienced cells (CD45RO). Further, ATG decreases CD2, CD3, CD4, and naïve (CD45RA) and stimulates T cells as translated by CD3CD69 and DR. As it should be expected from an IL-2αRAb agent, CD25 cells were virtually eliminated.
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Affiliation(s)
- P Xavier
- Portuguese Institute of Blood and Transplantation, Porto, Portugal.
| | - M Magalhães
- Department of Clinical Pathology, S. João Hospital Center, Porto, Portugal
| | - S Sampaio-Norton
- Department of Nephrology, S. João Hospital Center, Porto, Portugal
| | - T Guimarães
- Department of Clinical Pathology, S. João Hospital Center, Porto, Portugal
| | - J G Oliveira
- CINTESIS/Department of Medicine, Faculty of Medicine, University of Porto, Portugal
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Hendrawan K, Visweswaran M, Ma DDF, Moore JJ. Tolerance regeneration by T regulatory cells in autologous haematopoietic stem cell transplantation for autoimmune diseases. Bone Marrow Transplant 2019; 55:857-866. [PMID: 31619766 DOI: 10.1038/s41409-019-0710-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 09/22/2019] [Accepted: 09/23/2019] [Indexed: 12/29/2022]
Abstract
Autologous haematopoietic stem cell transplantation shows increasing promise as a therapeutic option for patients with treatment-refractory autoimmune disease, particularly systemic sclerosis and multiple sclerosis. However, this intensive chemotherapy-based procedure is not always possible due to potential treatment toxicities and comorbidities. The biological mechanisms of how this procedure induces long-term remission in autoimmune disease are increasingly understood. The focus of this review is on recent research findings on the role of CD4+ T regulatory cells (Tregs) in resetting the immune system leading to the eradication of the autoimmune disease after transplantation. Discovery of the precise mechanisms of this process will allow development of novel Treg-based therapies and thus avoid the need for intensive chemotherapy-based treatment for these autoimmune diseases in the future.
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Affiliation(s)
- Kevin Hendrawan
- Blood, Stem Cells and Cancer Research Programme, St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, 2011, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2010, Australia.,Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, 2010, Australia
| | - Malini Visweswaran
- Blood, Stem Cells and Cancer Research Programme, St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, 2011, Australia.,Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, 2010, Australia
| | - David D F Ma
- Blood, Stem Cells and Cancer Research Programme, St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, 2011, Australia.,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2010, Australia.,Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, 2010, Australia
| | - John J Moore
- Blood, Stem Cells and Cancer Research Programme, St Vincent's Centre for Applied Medical Research, Darlinghurst, NSW, 2011, Australia. .,St Vincent's Clinical School, Faculty of Medicine, University of New South Wales, Sydney, NSW, 2010, Australia. .,Department of Haematology, St Vincent's Hospital, Darlinghurst, NSW, 2010, Australia.
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Narita A, Zhu X, Muramatsu H, Chen X, Guo Y, Yang W, Zhang J, Liu F, Jang JH, Kook H, Kim H, Usuki K, Yamazaki H, Takahashi Y, Nakao S, Wook Lee J, Kojima S, the Aplastic Anaemia Working Party of the Asia‐Pacific Blood, Marrow Transplantation Group. Prospective randomized trial comparing two doses of rabbit anti‐thymocyte globulin in patients with severe aplastic anaemia. Br J Haematol 2019; 187:227-237. [DOI: 10.1111/bjh.16055] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 04/30/2019] [Indexed: 01/24/2023]
Abstract
SummaryThe treatment of choice for patients with severe aplastic anaemia (SAA) includes immunosuppressive therapy (IST) with anti‐thymocyte globulin (ATG) and ciclosporin A. However, the optimal dose for rabbit ATG has yet to be established. We herein report the first prospective, randomized, multicentre study comparing two doses of rabbit ATG in patients with SAA. Patients with SAA who required initial IST in Japan (n = 89), China (n = 85) and Korea (n = 48) were enrolled between May 2012 and October 2017. A 1:1 block randomization was employed for two doses of rabbit ATG. In total, 222 patients were randomized, with 112 patients receiving 2·5 mg/kg and 110 receiving 3·5 mg/kg of rabbit ATG for 5 days. The primary endpoint was the haematological response at day 180. After 6 months, no significant difference in response rates was observed between the 2·5 and 3·5 mg/kg groups (49% vs. 48%, P = 0·894). Overall survival at 3 years was similar between the two groups [85% (95% confidence interval [CI], 76%−91%) vs. 91% (95% CI, 82%−96%); P = 0·107]. The current study revealed no significant differences in the efficacy and safety between the 2·5 and 3·5 mg/kg doses of rabbit ATG in patients with SAA.Trial registration: UMIN000011134.
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Affiliation(s)
- Atsushi Narita
- Department of Paediatrics Nagoya University Graduate School of Medicine Nagoya Japan
| | - Xiaofan Zhu
- Department of Paediatrics Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin People’s Republic of China
| | - Hideki Muramatsu
- Department of Paediatrics Nagoya University Graduate School of Medicine Nagoya Japan
| | - Xiaojuan Chen
- Department of Paediatrics Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin People’s Republic of China
| | - Ye Guo
- Department of Paediatrics Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin People’s Republic of China
| | - Wenyu Yang
- Department of Paediatrics Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin People’s Republic of China
| | - Jingliao Zhang
- Department of Paediatrics Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin People’s Republic of China
| | - Fang Liu
- Department of Paediatrics Institute of Haematology and Blood Disease Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College Tianjin People’s Republic of China
| | - Jun H. Jang
- Department of Haematology Oncology Samsung Medical Centre, Sungkyunkwan University School of Medicine Seoul Republic of Korea
| | - Hoon Kook
- Department of Paediatrics Chonnam National University Hwasun Hospital, Chonnam National University Medical School Hwasun Republic of Korea
| | - Hawk Kim
- Division of Haematology Gachon University Gil Medical Centre, Gachon University College of Medicine Incheon Republic of Korea
| | - Kensuke Usuki
- Department of Haematology NTT Medical Centre Tokyo Tokyo Japan
| | - Hirohito Yamazaki
- Division of Transfusion Medicine Kanazawa University Hospital Kanazawa Japan
| | - Yoshiyuki Takahashi
- Department of Paediatrics Nagoya University Graduate School of Medicine Nagoya Japan
| | - Shinji Nakao
- Department of Haematology and Respirology Kanazawa University Graduate School of Medical Sciences Kanazawa Japan
| | - Jong Wook Lee
- Department of Haematology Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea Seoul Republic of Korea
| | - Seiji Kojima
- Department of Paediatrics Nagoya University Graduate School of Medicine Nagoya Japan
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Jamali S, Sarafnejad A, Ahmadpoor P, Nafar M, Karimi M, Eteghadi A, Yekaninejad MS, Amirzargar AA. Sirolimus vs mycophenolate moftile in Tacrolimus based therapy following induction with Antithymocyte globulin promotes regulatory T cell expansion and inhibits RORγt and T-bet expression in kidney transplantation. Hum Immunol 2019; 80:739-747. [PMID: 30597187 DOI: 10.1016/j.humimm.2018.12.010] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Revised: 12/05/2018] [Accepted: 12/28/2018] [Indexed: 11/30/2022]
Abstract
BACKGROUND Accumulating evidence suggests that regulatory T cells (Tregs) have a crucial role in immune tolerance and long-term graft survival. However, the influence of immunosuppressive drugs on the level of Tregs has not been fully understood. Therefore we prospectively compare the effect of two different calcineurin inhibitor (CNI)-based immunosuppression protocols on Tregs frequencies and expression of regulatory and effector T cell-related genes in renal transplant recipients. METHODS The study included 24 renal transplant recipients who received induction therapy (Antithymocyte globulin) and were on triple immunosuppressive therapy so that one group was on Tacrolimus (Tac), mycophenolate moftile (MMF) and prednisolone (P) whereas another group was on Tac, Sirolimus (SRL) and P. The frequency of circulating Treg cells was analyzed by flow cytometry before and 4 months after transplantation. Also, the mRNA expression of FOXP3, T-bet, GATA3 and RORγt was examined by quantitative RT-PCR before and 4 months after transplantation. RESULTS Compared to baseline, the frequency of CD4+ CD25+ FOXP3+ Treg cells was significantly increased in the all patients following transplantation. Patients who received Tac/MMF had significantly higher CD4+ CD25+ FOXP3+ Treg cells compared to patients who received Tac/SRL. There was no a significant difference in the frequency of CD3+CD8+ CD28- Tregs between two different calcineurin inhibitor (CNI)-based immunosuppression protocols. FOXP3 mRNA levels in the patients who received Tac/MMF were increased 4 months after transplantation and the expression was significantly higher than patients who received Tac/SRL. On the other hand, T-bet and RORγt expression levels were significantly lower in the Tac/SRL group in comparison to Tac/MMF group. We did not observe any significant difference in GATA3 mRNA level between the two groups. CONCLUSIONS Our results suggest that although Tac/MMF-containing immunosuppressive regimen could significantly increase the frequency of CD4+ CD25+ FOXP3+ Tregs, unlike to Tac/SRL-containing regimen, it could not significantly decrease the expression levels of RORγt and T-bet.
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Affiliation(s)
- Saeideh Jamali
- Department of Pathobiology, School of Public Healths, Tehran University of Medical Sciences, Tehran, Iran
| | - Abdolfatah Sarafnejad
- Department of Pathobiology, School of Public Healths, Tehran University of Medical Sciences, Tehran, Iran
| | - Pedram Ahmadpoor
- Chronic Kidney Disease Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohsen Nafar
- Chronic Kidney Disease Research Center, Labbafinejad Medical Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mozhdeh Karimi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Atefeh Eteghadi
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Mir Saeed Yekaninejad
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Iran
| | - Ali Akbar Amirzargar
- Department of Immunology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Molecular Immunology Research Center, Tehran University of Medical Sciences, Tehran, Iran.
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Lasmar MF, Dutra RS, Nogueira-Machado JA, Fabreti-Oliveira RA, Siqueira RG, Nascimento E. Effects of immunotherapy induction on outcome and graft survival of kidney-transplanted patients with different immunological risk of rejection. BMC Nephrol 2019; 20:314. [PMID: 31409321 PMCID: PMC6693276 DOI: 10.1186/s12882-019-1497-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2018] [Accepted: 07/26/2019] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND In kidney transplantation, immunotherapy with thymoglobulin (rATG) has been used to down-regulate the patient immune system. rATG is a powerful immunobiologic drug used to deplete lymphocytes to prevent early acute rejection. The aim of this research was to evaluate the effects of immunotherapy by rATG on graft suvival during a 9-year period in kidney-transplanted patients with different immunological profiles. METHODS A sample of 469 patients were allocated into four groups (G) based on immunological risk of rejection: G1, low risk, not sensitized recipients, solid-phase immunoassay with single antigen beads (SPI-SAB) < 10%; G2, medium risk I, sensitized recipients, SPI-SAB ≥ 10 < 50%; G3, medium risk II sensitized (SPI-SAB ≥50%); and G4, high risk, sensitized recipients, SPI-SAB- donor-specific antibody positive (DSA+). Only patients from G3 and G4 received immunotherapy. RESULTS Of 255 patients who received a kidney from a living donor (LD), 42 (16.47%) from all groups (G) had T-cell-mediated rejection (TCMR) and four (G1) lost their grafts, 8 (3.14%) had antibody-mediated rejection (AMR), and two lost their graft in G1 and G4. Of 214 patients who received a kidney from deceased donors (DD), 37 (17.29%) had TCMR with one lost graft in G1. AMR was shown in 13 (6.07%) patients, with three losses observed in G2. Statistical differences between the groups in the 9-year graft survival rate were found only in the comparison of G1 versus G2 (P = 0.005) and G2 versus G4 (P = 0.047) for DD. For LD, no statistical differences were found. CONCLUSION This clinical retrospective study shows that immunotherapy induction was associated with improvement of outcomes, graft function, and survival in patients treated with immunotherapy in comparison with patients who did not received induction therapy. These findings strongly suggest that immunotherapy should be used for all patients transplanted with kidneys from deceased donors.
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Affiliation(s)
- Marcus Faria Lasmar
- University Hospital of the Faculty of Medical Science, Belo Horizonte, Minas Gerais state Brazil
- Institute of Research and Education of the Hospital Santa Casa, Belo Horizonte, Minas Gerais state Brazil
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais State Brazil
| | - Rodrigo Santana Dutra
- University Hospital of the Faculty of Medical Science, Belo Horizonte, Minas Gerais state Brazil
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais State Brazil
| | | | - Raquel A. Fabreti-Oliveira
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais State Brazil
- IMUNOLAB – Laboratory of Histocompatibility, Minas Gerais state, Belo Horizonte, Brazil
| | | | - Evaldo Nascimento
- Faculty of Medical Sciences, Belo Horizonte, Minas Gerais State Brazil
- IMUNOLAB – Laboratory of Histocompatibility, Minas Gerais state, Belo Horizonte, Brazil
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47
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Ryba-Stanisławowska M, Sakowska J, Zieliński M, Ławrynowicz U, Trzonkowski P. Regulatory T cells: the future of autoimmune disease treatment. Expert Rev Clin Immunol 2019; 15:777-789. [PMID: 31104510 DOI: 10.1080/1744666x.2019.1620602] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Introduction: CD4 + T regulatory cells (Tregs) have been described as the most potent immunosuppressive cells in the human body. They have been found to control autoimmunity, and clinical attempts have been made to apply them to treat autoimmune diseases. Some specific pathways utilized by Tregs in the regulation of immune response or Tregs directly as cellular products are tested in the clinic. Areas covered: Here, we present recent advances in the research on the biology and clinical applications of Tregs in the treatment of autoimmune diseases. Expert opinion: Regulatory T cells seem to be a promising tool for the treatment of autoimmune diseases. The development of both cell-based therapies and modern pharmacotherapies which affect Tregs may strongly improve the treatment of autoimmune disorders. Growing knowledge about Treg biology together with the latest biotechnology tools may give an opportunity for personalized therapies in these conditions.
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Affiliation(s)
- Monika Ryba-Stanisławowska
- a Department of Medical Immunology , Laboratory of Experimental Immunology, Medical University of Gdańsk , Debinki , Poland
| | - Justyna Sakowska
- b Department of Medical Immunology , Medical University of Gdańsk , Debinki , Poland
| | - Maciej Zieliński
- b Department of Medical Immunology , Medical University of Gdańsk , Debinki , Poland
| | - Urszula Ławrynowicz
- a Department of Medical Immunology , Laboratory of Experimental Immunology, Medical University of Gdańsk , Debinki , Poland
| | - Piotr Trzonkowski
- a Department of Medical Immunology , Laboratory of Experimental Immunology, Medical University of Gdańsk , Debinki , Poland
- b Department of Medical Immunology , Medical University of Gdańsk , Debinki , Poland
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Ruszkowski J, Lisowska KA, Pindel M, Heleniak Z, Dębska-Ślizień A, Witkowski JM. T cells in IgA nephropathy: role in pathogenesis, clinical significance and potential therapeutic target. Clin Exp Nephrol 2019; 23:291-303. [PMID: 30406499 PMCID: PMC6394565 DOI: 10.1007/s10157-018-1665-0] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2018] [Accepted: 10/25/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Immunoglobulin A nephropathy (IgAN), the most frequent cause of primary glomerulonephritis worldwide, is an autoimmune disease with complex pathogenesis. In this review, we focus on T cells and summarize knowledge about their involvement in pathophysiology and treatment of IgAN METHODS: We reviewed the literature for (1) alterations of T cell subpopulations in IgAN, (2) experimental and clinical proofs for T cells' participation in IgAN pathogenesis, (3) clinical correlations with T cell-associated alterations, and (4) influence of drugs used in IgAN therapy on T cell subpopulations. RESULTS We found that IgAN is characterized by higher proportions of circulatory Th2, Tfh, Th17, Th22 and γδ T cells, but lower Th1 and Treg cells. We discuss genetic and epigenetic makeup that may contribute to this immunological phenotype. We found that Th2, Th17 and Tfh-type interleukins contribute to elevated synthesis of galactose-deficient IgA1 (Gd-IgA1) and that the production of anti-Gd-IgA1 autoantibodies may be stimulated by Tfh cells. We described the roles of Th2, Th17, Th22 and Treg cells in the renal injury and summarized correlations between T cell-associated alterations and clinical features of IgAN (proteinuria, reduced GFR, hematuria). We detailed the impact of immunosuppressive drugs on T cell subpopulations and found that the majority of drugs have nonoptimal influence on T cells in IgAN patients. CONCLUSIONS T cells play an important role in IgAN pathogenesis and are correlated with its clinical severity. Clinical trials with the drugs targeting the reported alterations of the T-cell compartment are highly desirable.
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Affiliation(s)
- Jakub Ruszkowski
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland.
| | - Katarzyna A Lisowska
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland
| | - Małgorzata Pindel
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland
| | - Zbigniew Heleniak
- Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Medicine, Faculty of Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Jacek M Witkowski
- Department of Pathophysiology, Faculty of Medicine, Medical University of Gdańsk, Dębinki 7, 80-211, Gdańsk, Poland
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Freitas GRR, da Luz Fernandes M, Agena F, Jaluul O, Silva SC, Lemos FBC, Coelho V, Elias DN, Galante NZ. Aging and End Stage Renal Disease Cause A Decrease in Absolute Circulating Lymphocyte Counts with A Shift to A Memory Profile and Diverge in Treg Population. Aging Dis 2019; 10:49-61. [PMID: 30705767 PMCID: PMC6345336 DOI: 10.14336/ad.2018.0318] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2018] [Accepted: 03/18/2018] [Indexed: 12/14/2022] Open
Abstract
There is a growing number of elderly kidney transplant (Ktx) recipients. Elderly recipients present lower acute rejection rates but higher incidence of infection and malignancies. Aging per se seems to result in a shift to memory profile and chronic kidney disease (CKD) in premature immunological aging. Understanding aging and CKD effects on the immune system can improve elderly Ktx immunosuppression. We analyzed the effects of aging and CKD in the immune system, comparing healthy adults (HAd) (n=14, 26±2y), healthy elderly (HEld) (n=15, 79±7y), end stage renal disease (ESRD) adults (EnAd) (n=18, 36±7y) and ESRD elderly (EnEld) (n=31, 65±3y) prior to Ktx regarding their naïve, memory and regulatory T and B peripheral lymphocytes. Aging and ESRD presented additive effect decreasing absolute numbers of B and T-lymphocytes, affecting memory, naive and regulatory subsets without synergic effect. Both resulted in higher percentages of T memory subsets and opposing effects on regulatory T (TREG) subsets, higher percentage in aging and lower in ESRD. Combined effect of aging and ESRD also resulted in higher regulatory B cell percentages. In addition to global lymphopenia and TCD4+ memory shift in both aging and ESRD, aging shifts to an immunoregulatory profile, inducing a increase in TREG percentages, contrasting with ESRD that decreases TREGs. Differential immunosuppression regimens for elderly Ktx may be required. (ClinicalTrials.gov number: NTC01631058).
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Affiliation(s)
- Geraldo Rubens Ramos Freitas
- 1Division of Nephrology, and.,2Renal Transplant Service, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Maria da Luz Fernandes
- 2Renal Transplant Service, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Fabiana Agena
- 2Renal Transplant Service, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Omar Jaluul
- 3Division of Geriatrics, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Sérgio Colenci Silva
- 3Division of Geriatrics, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | | | - Verônica Coelho
- 4Laboratory of Immunology, Heart Institute, University of Sao Paulo School of Medicine. Institute for Investigation in Immunology, Sao Paulo, Brazil
| | - David-Neto Elias
- 2Renal Transplant Service, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
| | - Nelson Zocoler Galante
- 2Renal Transplant Service, Hospital das Clinicas, University of Sao Paulo School of Medicine, Sao Paulo, Brazil
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