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Zimmerer JM, Chaudhari S, Koneru K, Han JL, Abdel-Rasoul M, Uwase H, Yi T, Breuer CK, Bumgardner GL. Germinal Center B Cells are Uniquely Targeted by Antibody-Suppressor CXCR5 +CD8 + T Cells. Transplant Direct 2025; 11:e1742. [PMID: 39802197 PMCID: PMC11723704 DOI: 10.1097/txd.0000000000001742] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Revised: 10/16/2024] [Accepted: 10/31/2024] [Indexed: 01/16/2025] Open
Abstract
Background Alloprimed antibody-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp cells) downregulate alloantibody production, mediate cytotoxicity of IgG+ B cells, and prolong allograft survival. The purpose of this investigation was to determine which immune-cell subsets are susceptible to CD8+ TAb-supp cell-mediated cytotoxicity or noncytotoxic suppression. Methods Alloprimed immune-cell subsets were evaluated for susceptibility to CD8+ TAb-supp cell-mediated in vitro cytotoxicity and/or suppression of intracellular cytokine expression. In vivo CD8-mediated cytotoxicity to wild-type germinal center (GC) B cells or wild-type CD4+ T follicular helper cells (TFH cells) was assessed in RAG1 knockout mice. The impact of in vivo adoptive transfer of CD8+ TAb-supp cells into hepatocyte or kidney transplant recipients on the quantity of lymphoid immune-cell subsets was assessed. Results CD8+ TAb-supp cells mediated allospecific cytotoxicity to alloprimed GC B cells but not alloprimed extrafollicular plasmablasts, marginal zone B cells, follicular B cells, or plasma cells. CD8+ TAb-supp cells did not mediate cytotoxicity to alloprimed dendritic cells, macrophages, CD4+ TFH cells, CD4+ T follicular regulatory cells, or CD4+ regulatory T cell. CD8+ TAb-supp cells did not suppress CD4+ TFH cell, T follicular regulatory cell, or regulatory T-cell cytokine expression. Adoptive transfer of CD8+ TAb-supp cells into hepatocyte or kidney transplant recipients reduced alloantibody production and the quantity of GC B cells, TFH cells, and plasma cells (but not other B-cell, T-cell, or antigen-presenting cell subsets). The reduction of TFH-cell quantity was dependent on CD8+ TAb-supp cell-mediated major histocompatibility complex-I-dependent cytotoxic killing of GC B cells. Conclusions The primary targets of CD8+ TAb-supp cells are GC B cells with downstream reduction of TFH and plasma cells.
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Affiliation(s)
- Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Sachi Chaudhari
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Kavya Koneru
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Jing L. Han
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
- Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH
| | - Mahmoud Abdel-Rasoul
- Department of Biomedical Informatics, Center for Biostatistics, The Ohio State University, Columbus, OH
| | - Hope Uwase
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Tai Yi
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Christopher K. Breuer
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
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Tian S, Goand UK, Paudel D, Le GV, Tiwari AK, Prabhu KS, Singh V. Processed Dietary Fiber Partially Hydrolyzed Guar Gum Increases Susceptibility to Colitis and Colon Tumorigenesis in Mice. RESEARCH SQUARE 2024:rs.3.rs-5522559. [PMID: 39711544 PMCID: PMC11661293 DOI: 10.21203/rs.3.rs-5522559/v1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2024]
Abstract
The vital role of naturally occurring dietary fibers (DFs) in maintaining intestinal health has fueled the incorporation of isolated DFs into processed foods. A select group of soluble DFs, such as partially hydrolyzed guar gum (Phgg), are being promoted as dietary supplements to meet recommended DF intake. However, the potential effects of regular consumption of these processed DFs on gastrointestinal health remain largely unknown. The present study assessed the impact of Phgg on the development of intestinal inflammation and colitis-associated colon carcinogenesis (CAC). Wild-type C57BL/6 mice were fed isocaloric diets containing either 7.5% Phgg and 2.5% cellulose (Phgg group) or 10% cellulose (control) for four weeks. To induce colitis, a subgroup of mice from each group was switched to 1.4% dextran sulfate sodium (DSS) in drinking water for seven days. CAC was induced in another subgroup through a single dose of azoxymethane (AOM, 7.5 mg/kg i.p.) followed by three DSS/water cycles. To our surprise, Phgg feeding exacerbated DSS-induced colitis, as evidenced by body weight loss, disrupted colonic crypt architecture, and increased pro-inflammatory markers accompanied by a decrease in anti-inflammatory markers. Additionally, Phgg feeding led to increased colonic expression of genes promoting cell proliferation. Accordingly, extensive colon tumorigenesis was observed in Phgg-fed mice in the AOM/DSS model, whereas the control group exhibited no visible tumors. To investigate whether reducing Phgg has a distinct effect on colitis and CAC development, mice were fed a low-Phgg diet (2.5% Phgg). The low-Phgg group also exhibited increased colitis and tumorigenesis compared to the control, although the severity was markedly lower than in the regular Phgg (7.5%) group, suggesting a dose-dependent effect of Phgg in colitis and CAC development. Our study reveals that Phgg supplementation exacerbates colitis and promotes colon tumorigenesis, warranting further investigation into the potential gastrointestinal health risks associated with processed Phgg consumption.
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Nicosia M, Valujskikh A. Recognizing Complexity of CD8 T Cells in Transplantation. Transplantation 2024; 108:2186-2196. [PMID: 38637929 PMCID: PMC11489323 DOI: 10.1097/tp.0000000000005001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/20/2024]
Abstract
The major role of CD8 + T cells in clinical and experimental transplantation is well documented and acknowledged. Nevertheless, the precise impact of CD8 + T cells on graft tissue injury is not completely understood, thus impeding the development of specific treatment strategies. The goal of this overview is to consider the biology and functions of CD8 + T cells in the context of experimental and clinical allotransplantation, with special emphasis on how this cell subset is affected by currently available and emerging therapies.
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Affiliation(s)
- Michael Nicosia
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
| | - Anna Valujskikh
- Department of Inflammation and Immunity, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio 44195, USA
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Ismail AM, Witt E, Bouwman T, Clark W, Yates B, Franco M, Fong S. The longitudinal kinetics of AAV5 vector integration profiles and evaluation of clonal expansion in mice. Mol Ther Methods Clin Dev 2024; 32:101294. [PMID: 39104575 PMCID: PMC11298592 DOI: 10.1016/j.omtm.2024.101294] [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: 03/28/2024] [Accepted: 06/24/2024] [Indexed: 08/07/2024]
Abstract
Adeno-associated virus (AAV)-based vectors are used clinically for gene transfer and persist as extrachromosomal episomes. A small fraction of vector genomes integrate into the host genome, but the theoretical risk of tumorigenesis depends on vector regulatory features. A mouse model was used to investigate integration profiles of an AAV serotype 5 (AAV5) vector produced using Sf and HEK293 cells that mimic key features of valoctocogene roxaparvovec (AAV5-hFVIII-SQ), a gene therapy for severe hemophilia A. The majority (95%) of vector genome reads were derived from episomes, and mean (± standard deviation) integration frequency was 2.70 ± 1.26 and 1.79 ± 0.86 integrations per 1,000 cells for Sf- and HEK293-produced vector. Longitudinal integration analysis suggested integrations occur primarily within 1 week, at low frequency, and their abundance was stable over time. Integration profiles were polyclonal and randomly distributed. No major differences in integration profiles were observed for either vector production platform, and no integrations were associated with clonal expansion. Integrations were enriched near transcription start sites of genes highly expressed in the liver (p = 1 × 10-4) and less enriched for genes of lower expression. We found no evidence of tumorigenesis or fibrosis caused by the vector integrations.
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Affiliation(s)
| | - Evan Witt
- BioMarin Pharmaceutical Inc., Novato, CA 94949, USA
| | | | - Wyatt Clark
- BioMarin Pharmaceutical Inc., Novato, CA 94949, USA
| | | | - Matteo Franco
- ProtaGene CGT GmbH, Heidelberg 69120, Germany
- ProtaGene Inc., Burlington, MA 01803, USA
| | - Sylvia Fong
- BioMarin Pharmaceutical Inc., Novato, CA 94949, USA
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Han JL, Zimmerer JM, Zeng Q, Chaudhari S, Satoskar A, Abdel-Rasoul M, Uwase H, Breuer CK, Bumgardner GL. Antibody-Suppressor CXCR5+CD8+ T Cells Are More Potent Regulators of Humoral Alloimmunity after Kidney Transplant in Mice Compared to CD4+ Regulatory T Cells. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2024; 212:1504-1518. [PMID: 38517294 PMCID: PMC11047759 DOI: 10.4049/jimmunol.2300289] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Accepted: 02/27/2024] [Indexed: 03/23/2024]
Abstract
Adoptive cell therapy (ACT), especially with CD4+ regulatory T cells (CD4+ Tregs), is an emerging therapeutic strategy to minimize immunosuppression and promote long-term allograft acceptance, although much research remains to realize its potential. In this study, we investigated the potency of novel Ab-suppressor CXCR5+CD8+ T cells (CD8+ TAb-supp) in comparison with conventional CD25highFoxp3+CD4+ Tregs for suppression of humoral alloimmunity in a murine kidney transplant (KTx) model of Ab-mediated rejection (AMR). We examined quantity of peripheral blood, splenic and graft-infiltrating CD8+ TAb-supp, and CD4+ Tregs in KTx recipients and found that high alloantibody-producing CCR5 knockout KTx recipients have significantly fewer post-transplant peripheral blood and splenic CD8+ TAb-supp, as well as fewer splenic and graft-infiltrating CD4+ Tregs compared with wild-type KTx recipients. ACT with alloprimed CXCR5+CD8+ T cells reduced alloantibody titer, splenic alloprimed germinal center (GC) B cell quantity, and improved AMR histology in CCR5 knockout KTx recipients. ACT with alloprimed CD4+ Treg cells improved AMR histology without significantly inhibiting alloantibody production or the quantity of splenic alloprimed GC B cells. Studies with TCR transgenic mice confirmed Ag specificity of CD8+ TAb-supp-mediated effector function. In wild-type recipients, CD8 depletion significantly increased alloantibody titer, GC B cells, and severity of AMR pathology compared with isotype-treated controls. Anti-CD25 mAb treatment also resulted in increased but less pronounced effect on alloantibody titer, quantity of GC B cells, and AMR pathology than CD8 depletion. To our knowledge, this is the first report that CD8+ TAb-supp cells are more potent regulators of humoral alloimmunity than CD4+ Treg cells.
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Affiliation(s)
- Jing L. Han
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
- Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH
| | - Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Qiang Zeng
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Sachi Chaudhari
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Anjali Satoskar
- Department of Pathology, The Ohio State University, Columbus, OH
| | | | - Hope Uwase
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - Christopher K. Breuer
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
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Koh CH, Lee S, Kwak M, Kim BS, Chung Y. CD8 T-cell subsets: heterogeneity, functions, and therapeutic potential. Exp Mol Med 2023; 55:2287-2299. [PMID: 37907738 PMCID: PMC10689838 DOI: 10.1038/s12276-023-01105-x] [Citation(s) in RCA: 92] [Impact Index Per Article: 46.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2023] [Revised: 08/11/2023] [Accepted: 08/12/2023] [Indexed: 11/02/2023] Open
Abstract
CD8 T cells play crucial roles in immune surveillance and defense against infections and cancer. After encountering antigenic stimulation, naïve CD8 T cells differentiate and acquire effector functions, enabling them to eliminate infected or malignant cells. Traditionally, cytotoxic T cells, characterized by their ability to produce effector cytokines and release cytotoxic granules to directly kill target cells, have been recognized as the constituents of the predominant effector T-cell subset. However, emerging evidence suggests distinct subsets of effector CD8 T cells that each exhibit unique effector functions and therapeutic potential. This review highlights recent advancements in our understanding of CD8 T-cell subsets and the contributions of these cells to various disease pathologies. Understanding the diverse roles and functions of effector CD8 T-cell subsets is crucial to discern the complex dynamics of immune responses in different disease settings. Furthermore, the development of immunotherapeutic approaches that specifically target and regulate the function of distinct CD8 T-cell subsets holds great promise for precision medicine.
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Affiliation(s)
- Choong-Hyun Koh
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
| | - Suyoung Lee
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Minkyeong Kwak
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea
| | - Byung-Seok Kim
- Division of Life Sciences, College of Life Science and Bioengineering, Incheon National University, Incheon, 22012, Republic of Korea
| | - Yeonseok Chung
- Laboratory of Immune Regulation, Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul, 08826, Republic of Korea.
- BK21 Plus Program, College of Pharmacy, Seoul National University, Seoul, 08826, Republic of Korea.
- Wide River Institute of Immunology, Seoul National University, Hongcheon, Gangwon, 25159, Republic of Korea.
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Zimmerer JM, Han JL, Peterson CM, Zeng Q, Ringwald BA, Cassol C, Chaudhari S, Hart M, Hemminger J, Satoskar A, Abdel-Rasoul M, Wang JJ, Warren RT, Zhang ZJ, Breuer CK, Bumgardner GL. Antibody-suppressor CXCR5 + CD8 + T cellular therapy ameliorates antibody-mediated rejection following kidney transplant in CCR5 KO mice. Am J Transplant 2022; 22:1550-1563. [PMID: 35114045 PMCID: PMC9177711 DOI: 10.1111/ajt.16988] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/10/2022] [Accepted: 01/29/2022] [Indexed: 01/25/2023]
Abstract
CCR5 KO kidney transplant (KTx) recipients are extraordinarily high alloantibody producers and develop pathology that mimics human antibody-mediated rejection (AMR). C57BL/6 and CCR5 KO mice (H-2b ) were transplanted with A/J kidneys (H-2a ); select cohorts received adoptive cell therapy (ACT) with alloprimed CXCR5+ CD8+ T cells (or control cells) on day 5 after KTx. ACT efficacy was evaluated by measuring posttransplant alloantibody, pathology, and allograft survival. Recipients were assessed for the quantity of CXCR5+ CD8+ T cells and CD8-mediated cytotoxicity to alloprimed IgG+ B cells. Alloantibody titer in CCR5 KO recipients was four-fold higher than in C57BL/6 recipients. The proportion of alloprimed CXCR5+ CD8+ T cells 7 days after KTx in peripheral blood, lymph node, and spleen was substantially lower in CCR5 KO compared to C57BL/6 recipients. In vivo cytotoxicity towards alloprimed IgG+ B cells was also reduced six-fold in CCR5 KO recipients. ACT with alloprimed CXCR5+ CD8+ T cells (but not alloprimed CXCR5- CD8+ or third-party primed CXCR5+ CD8+ T cells) substantially reduced alloantibody titer, ameliorated AMR pathology, and prolonged allograft survival. These results indicate that a deficiency in quantity and function of alloprimed CXCR5+ CD8+ T cells contributes to high alloantibody and AMR in CCR5 KO recipient mice, which can be rescued with ACT.
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Affiliation(s)
- Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Jing L. Han
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH,Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH
| | - Chelsea M. Peterson
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Qiang Zeng
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Bryce A. Ringwald
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Clarissa Cassol
- Department of Pathology, The Ohio State University, Columbus, OH
| | - Sachi Chaudhari
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Madison Hart
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | | | - Anjali Satoskar
- Department of Pathology, The Ohio State University, Columbus, OH
| | | | - Jiao-Jing Wang
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Robert T. Warren
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Zheng J. Zhang
- Department of Surgery, Comprehensive Transplant Center, Northwestern University Feinberg School of Medicine, Chicago, IL
| | - Christopher K. Breuer
- Center for Regenerative Medicine, The Research Institute at Nationwide Children’s Hospital, Columbus, OH
| | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
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Elzein SM, Zimmerer JM, Han JL, Ringwald BA, Bumgardner GL. CXCR5 +CD8 + T cells: A Review of their Antibody Regulatory Functions and Clinical Correlations. THE JOURNAL OF IMMUNOLOGY 2021; 206:2775-2783. [PMID: 34602651 DOI: 10.4049/jimmunol.2100082] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
CD8+ T cells have conventionally been studied in relationship to pathogen or tumor clearance. Recent reports have identified novel functions of CXCR5+CD8+ T cells that can home to lymphoid follicles, a key site of antibody production. In this review we provide an in-depth analysis of conflicting reports regarding the impact of CXCR5+CD8+ T cells on antibody production and examine the data supporting a role for antibody-enhancement (B cell "helper") and antibody-downregulation (antibody-suppressor) by CXCR5+CD8+ T cell subsets. CXCR5+CD8+ T cell molecular phenotypes are associated with CD8-mediated effector functions including distinct subsets that regulate antibody responses. Co-inhibitory molecule PD-1, among others, distinguish CXCR5+CD8+ T cell subsets. We also provide the first in-depth review of human CXCR5+CD8+ T cells in the context of clinical outcomes and discuss the potential utility of monitoring the quantity of peripheral blood or tissue infiltrating CXCR5+CD8+ T cells as a prognostic tool in multiple disease states.
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Affiliation(s)
- Steven M Elzein
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Jason M Zimmerer
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Jing L Han
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH.,Biomedical Sciences Graduate Program, The Ohio State University College of Medicine, Columbus, OH
| | - Bryce A Ringwald
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Ginny L Bumgardner
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
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CXCR5+IFN-γ+CD8+ T Lymphocytes as a Potential Inhibitor of DSA Formation in Renal Transplant Recipients. Transplantation 2020; 104:2264-2265. [PMID: 33125205 DOI: 10.1097/tp.0000000000003152] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Kwun J, Knechtle S. Experimental modeling of desensitization: What have we learned about preventing AMR? Am J Transplant 2020; 20 Suppl 4:2-11. [PMID: 32538533 PMCID: PMC7522789 DOI: 10.1111/ajt.15873] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2020] [Revised: 03/06/2020] [Accepted: 03/09/2020] [Indexed: 01/25/2023]
Abstract
During the past 5 decades, short-term outcomes in kidney transplant have significantly improved, in large part due to reduced rates and severity of acute rejection. Development of better immunosuppressive maintenance agents, as well as new induction therapies, helped make these advances. Nonhuman primate models provided a rigorous testing platform to evaluate candidate biologics during this process. However, antibody-mediated rejection remains a major cause of late failure of kidney allografts despite advances made in pharmacologic immunosuppression and strategies developed to facilitate improved donor-recipient matching. Our laboratory has been actively working to develop strategies to prevent and treat antibody-mediated rejection and immunologic sensitization in organ transplant, relying largely on a nonhuman primate model of kidney transplant. In this review, we will cover outcomes achieved by managing antibody-mediated rejection or sensitization in nonhuman primate models and discuss promises, limitations, and future directions for this model.
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Affiliation(s)
- Jean Kwun
- Address all correspondence and requests for reprints to: Jean Kwun, PhD, 207 Research Drive, Jones 362, DUMC Box 2645, Durham, NC 27710, USA Phone: 919-668-6792; Fax: 919-684-8716;
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Inverse Association Between the Quantity of Human Peripheral Blood CXCR5+IFN-γ+CD8+ T Cells With De Novo DSA Production in the First Year After Kidney Transplant. Transplantation 2020; 104:2424-2434. [PMID: 32032292 DOI: 10.1097/tp.0000000000003151] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND We recently reported that a novel CXCR5IFN-γCD8 T-cell subset significantly inhibits posttransplant alloantibody production in a murine transplant model. These findings prompted the current study to investigate the association of human CD8 T cells with the same phenotype with the development of de novo donor-specific antibody (DSA) after kidney transplantation. METHODS In the current studies, we prospectively and serially analyzed peripheral blood CD8 and CD4 T-cell subsets and monitored for the development of de novo DSA in kidney transplant recipients during the first-year posttransplant. We report results on 95 first-time human kidney transplant recipients with 1-year follow-up. RESULTS Twenty-three recipients (24.2%) developed de novo DSA within 1-year posttransplant. Recipients who developed DSA had significantly lower quantities of peripheral CXCR5IFN-γCD8 T cells (P = 0.01) and significantly lower ratios of CXCR5IFN-γCD8 T cell to combined CD4 Th1/Th2 cell subsets (IFN-γCD4 and IL-4CD4 cells; P = 0.0001) compared to recipients who remained DSA-negative over the first-year posttransplant. CONCLUSIONS Our data raise the possibility that human CXCR5IFN-γCD8 T cells are a homolog to murine CXCR5IFN-γCD8 T cells (termed antibody-suppressor CD8 T cells) and that the quantity of CXCR5IFN-γCD8 T cells (or the ratio of CXCR5IFN-γCD8 T cells to Th1/Th2 CD4 T cells) may identify recipients at risk for development of DSA.
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Zimmerer JM, Ringwald BA, Elzein SM, Avila CL, Warren RT, Abdel-Rasoul M, Bumgardner GL. Antibody-suppressor CD8+ T Cells Require CXCR5. Transplantation 2019; 103:1809-1820. [PMID: 30830040 PMCID: PMC6713619 DOI: 10.1097/tp.0000000000002683] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
BACKGROUND We previously reported the novel activity of alloprimed CD8 T cells that suppress posttransplant alloantibody production. The purpose of the study is to investigate the expression and role of CXCR5 on antibody-suppressor CD8 T-cell function. METHODS C57BL/6 mice were transplanted with FVB/N hepatocytes. Alloprimed CD8 T cells were retrieved on day 7 from hepatocyte transplant recipients. Unsorted or flow-sorted (CXCR5CXCR3 and CXCR3CXCR5) alloprimed CD8 T-cell subsets were analyzed for in vitro cytotoxicity and capacity to inhibit in vivo alloantibody production following adoptive transfer into C57BL/6 or high alloantibody-producing CD8 knock out (KO) hepatocyte transplant recipients. Alloantibody titer was assessed in CD8 KO mice reconstituted with naive CD8 T cells retrieved from C57BL/6, CXCR5 KO, or CXCR3 KO mice. Antibody suppression by ovalbumin (OVA)-primed monoclonal OVA-specific t-cell receptor transgenic CD8+ T cells (OT-I) CXCR5 or CXCR3 CD8 T-cell subsets was also investigated. RESULTS Alloprimed CXCR5CXCR3CD8 T cells mediated in vitro cytotoxicity of alloprimed "self" B cells, while CXCR3CXCR5CD8 T cells did not. Only flow-sorted alloprimed CXCR5CXCR3CD8 T cells (not flow-sorted alloprimed CXCR3CXCR5CD8 T cells) suppressed alloantibody production and enhanced graft survival when transferred into transplant recipients. Unlike CD8 T cells from wild-type or CXCR3 KO mice, CD8 T cells from CXCR5 KO mice do not develop alloantibody-suppressor function. Similarly, only flow-sorted CXCR5CXCR3 (and not CXCR3CXCR5) OVA-primed OT-I CD8 T cells mediated in vivo suppression of anti-OVA antibody production. CONCLUSIONS These data support the conclusion that expression of CXCR5 by antigen-primed CD8 T cells is critical for the function of antibody-suppressor CD8 T cells.
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Affiliation(s)
- Jason M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Bryce A. Ringwald
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Steven M. Elzein
- Medical Student Research Program, The Ohio State University College of Medicine, Columbus, OH
| | - Christina L. Avila
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - Robert T. Warren
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | | | - Ginny L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
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Zimmerer JM, Liu XL, Blaszczak A, Avila CL, Pham TA, Warren RT, Bumgardner GL. Critical Role of Macrophage FcγR Signaling and Reactive Oxygen Species in Alloantibody-Mediated Hepatocyte Rejection. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2018; 201:3731-3740. [PMID: 30397035 PMCID: PMC6289737 DOI: 10.4049/jimmunol.1800333] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/06/2018] [Accepted: 10/03/2018] [Indexed: 12/24/2022]
Abstract
Humoral alloimmunity negatively impacts both short- and long-term cell and solid organ transplant survival. We previously reported that alloantibody-mediated rejection of transplanted hepatocytes is critically dependent on host macrophages. However, the effector mechanism(s) of macrophage-mediated injury to allogeneic liver parenchymal cells is not known. We hypothesized that macrophage-mediated destruction of allogeneic hepatocytes occurs by cell-cell interactions requiring FcγRs. To examine this, alloantibody-dependent hepatocyte rejection in CD8-depleted wild-type (WT) and Fcγ-chain knockout (KO; lacking all functional FcγR) transplant recipients was evaluated. Alloantibody-mediated hepatocellular allograft rejection was abrogated in recipients lacking FcγR compared with WT recipients. We also investigated anti-FcγRI mAb, anti-FcγRIII mAb, and inhibitors of intracellular signaling (to block phagocytosis, cytokines, and reactive oxygen species [ROS]) in an in vitro alloantibody-dependent, macrophage-mediated hepatocytoxicity assay. Results showed that in vitro alloantibody-dependent, macrophage-mediated hepatocytotoxicity was critically dependent on FcγRs and ROS. The adoptive transfer of WT macrophages into CD8-depleted FcγR-deficient recipients was sufficient to induce alloantibody-mediated rejection, whereas adoptive transfer of macrophages from Fcγ-chain KO mice or ROS-deficient (p47 KO) macrophages was not. These results provide the first evidence, to our knowledge, that alloantibody-dependent hepatocellular allograft rejection is mediated by host macrophages through FcγR signaling and ROS cytotoxic effector mechanisms. These results support the investigation of novel immunotherapeutic strategies targeting macrophages, FcγRs, and/or downstream molecules, including ROS, to inhibit humoral immune damage of transplanted hepatocytes and perhaps other cell and solid organ transplants.
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Affiliation(s)
- Jason M Zimmerer
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and
| | - Xin L Liu
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and
| | - Alecia Blaszczak
- Medical Scientist Training Program, College of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH 43210
| | - Christina L Avila
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and
| | - Thomas A Pham
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and
| | - Robert T Warren
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and
| | - Ginny L Bumgardner
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University Wexner Medical Center, Columbus, OH 43210; and
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Abstract
Crosstalk between B and T cells in transplantation is increasingly recognized as being important in the alloimmune response. T cell activation of B cells occurs by a 3-stage pathway, culminating with costimulation signals. We review the distinct T cell subtypes required for B-cell activation and discuss the formation of the germinal center (GC) after transplantation, with particular reference to the repopulation of the GC after depletional induction, and the subsequent effect of immunosuppressive manipulation of T cell-B cell interactions. In addition, ectopic GCs are seen in transplantation, but their role is not fully understood. Therapeutic options to target T cell-B cell interactions are of considerable interest, both as immunosuppressive tools, and to aid in the further understanding of these important alloimmune mechanisms.
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Abstract
BACKGROUND The liver immune environment is tightly regulated to balance immune activation with immune tolerance. Understanding the dominant immune pathways initiated in the liver is important because the liver is a site for cell transplantation, such as for islet and hepatocyte transplantation. The purpose of this study is to examine the consequences of alloimmune stimulation when allogeneic cells are transplanted to the liver in comparison to a different immune locale, such as the kidney. METHODS We investigated cellular and humoral immune responses when allogeneic hepatocytes are transplanted directly to the recipient liver by intraportal injection. A heterotopic kidney engraftment site was used for comparison to immune activation in the liver microenvironment. RESULTS Transplantation of allogeneic hepatocytes delivered directly to the liver, via recipient portal circulation, stimulated long-term, high magnitude CD8 T cell-mediated allocytotoxicity. CD8 T cells initiated significant in vivo allocytotoxicity as well as rapid rejection of hepatocytes transplanted to the liver even in the absence of secondary lymph nodes or CD4 T cells. In contrast, in the absence of recipient peripheral lymphoid tissue and CD4 T cells, CD8-mediated in vivo allocytotoxicity was abrogated, and rejection was delayed when hepatocellular allografts were transplanted to the kidney subcapsular site. CONCLUSIONS These results highlight the CD8-dominant proinflammatory immune responses unique to the liver microenvironment. Allogeneic cells transplanted directly to the liver do not enjoy immune privilege but rather require immunosuppression to prevent rejection by a robust and persistent CD8-dependent allocytotoxicity primed in the liver.
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mTOR Inhibition Suppresses Posttransplant Alloantibody Production Through Direct Inhibition of Alloprimed B Cells and Sparing of CD8+ Antibody-Suppressing T cells. Transplantation 2017; 100:1898-906. [PMID: 27362313 DOI: 10.1097/tp.0000000000001291] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND De novo alloantibodies (donor-specific antibody) contribute to antibody-mediated rejection and poor long-term graft survival. Because the development of donor-specific antibody is associated with early graft loss of cell transplants and reduced long-term survival of solid organ transplants, we hypothesized that conventional immunosuppressives, calcineurin inhibitors (CNi), and mammalian target of rapamycin inhibitors (mTORi), may not be as effective for suppression of humoral alloimmunity as for cell-mediated immunity. METHODS Wild-type or CD8-depleted mice were transplanted with allogeneic hepatocytes. Recipients were treated with mTORi and/or CNi and serially monitored for alloantibody and graft survival. The direct effect of mTORi and CNi on alloprimed B cell function was investigated in Rag1 mice adoptively transferred with alloprimed IgG1 B cells. The efficacy of mTORi and/or CNi to suppress CD8-mediated cytotoxicity of IgG1 B cells was evaluated in in vitro and in vivo cytotoxicity assays. RESULTS Mammalian target of rapamycin inhibitors, but not CNi, reduced alloantibody production in transplant recipients, directly suppressed alloantibody production by alloprimed IgG1 B cells and delayed graft rejection in both low and high alloantibody producers. Combination treatment with mTORi and CNi resulted in loss of the inhibitory effect observed for mTORi monotherapy in part due to CNi suppression of CD8 T cells which downregulate alloantibody production (CD8 TAb-supp cells). CONCLUSIONS Our data support that mTORi is a potent inhibitor of humoral immunity through suppression of alloprimed B cells and preservation of CD8 TAb-supp cells. In contrast, alloantibody is readily detected in CNi-treated recipients because CNi does not suppress alloprimed B cells and interferes with downregulatory CD8 TAb-supp cells.
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Natural killer cells play a critical role in mediating inflammation and graft failure during antibody-mediated rejection of kidney allografts. Kidney Int 2016; 89:1293-306. [PMID: 27165816 DOI: 10.1016/j.kint.2016.02.030] [Citation(s) in RCA: 58] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2015] [Revised: 01/11/2016] [Accepted: 02/04/2016] [Indexed: 12/14/2022]
Abstract
While the incidence of antibody-mediated kidney graft rejection has increased, the key cellular and molecular participants underlying this graft injury remain unclear. Rejection of kidney allografts in mice lacking the chemokine receptor CCR5 is dependent on production of donor-specific antibody. Here we determine if cells expressing cytotoxic function contributed to antibody-mediated kidney allograft rejection in these recipients. Wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) mice were transplanted with complete MHC-mismatched A/J kidney grafts, and intragraft inflammatory components were followed to rejection. B6.CCR5(-/-) and B6.CD8(-/-)/CCR5(-/-) recipients rejected kidney allografts by day 35, whereas 65% of allografts in wild-type recipients survived past day 80 post-transplant. Rejected allografts in wild-type C57BL/6, B6.CCR5(-/-), and B6.CD8(-/-)/CCR5(-/-) recipients expressed high levels of VCAM-1 and MMP7 mRNA that was associated with high serum titers of donor-specific antibody. High levels of perforin and granzyme B mRNA expression peaked on day 6 post-transplant in allografts in all recipients, but were absent in isografts. Depletion of natural killer cells in B6.CD8(-/-)/CCR5(-/-) recipients reduced this expression to background levels and promoted the long-term survival of 40% of the kidney allografts. Thus, natural killer cells have a role in increased inflammation during antibody-mediated kidney allograft injury and in rejection of the grafts.
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Oldhafer F, Bock M, Falk CS, Vondran FWR. Immunological aspects of liver cell transplantation. World J Transplant 2016; 6:42-53. [PMID: 27011904 PMCID: PMC4801804 DOI: 10.5500/wjt.v6.i1.42] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/31/2015] [Revised: 10/21/2015] [Accepted: 12/08/2015] [Indexed: 02/05/2023] Open
Abstract
Within the field of regenerative medicine, the liver is of major interest for adoption of regenerative strategies due to its well-known and unique regenerative capacity. Whereas therapeutic strategies such as liver resection and orthotopic liver transplantation (OLT) can be considered standards of care for the treatment of a variety of liver diseases, the concept of liver cell transplantation (LCTx) still awaits clinical breakthrough. Success of LCTx is hampered by insufficient engraftment/long-term acceptance of cellular allografts mainly due to rejection of transplanted cells. This is in contrast to the results achieved for OLT where long-term graft survival is observed on a regular basis and, hence, the liver has been deemed an immune-privileged organ. Immune responses induced by isolated hepatocytes apparently differ considerably from those observed following transplantation of solid organs and, thus, LCTx requires refined immunological strategies to improve its clinical outcome. In addition, clinical usage of LCTx but also related basic research efforts are hindered by the limited availability of high quality liver cells, strongly emphasizing the need for alternative cell sources. This review focuses on the various immunological aspects of LCTx summarizing data available not only for hepatocyte transplantation but also for transplantation of non-parenchymal liver cells and liver stem cells.
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Zhang W, Luo X, Zhang F, Zhu Y, Yang B, Hou M, Xu Z, Yu C, Chen Y, Chen L, Ji M. SjTat-TPI facilitates adaptive T-cell responses and reduces hepatic pathology during Schistosoma japonicum infection in BALB/c mice. Parasit Vectors 2015; 8:664. [PMID: 26714844 PMCID: PMC4696208 DOI: 10.1186/s13071-015-1275-6] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Accepted: 12/18/2015] [Indexed: 12/18/2022] Open
Abstract
Background Schistosomiasis is a kind of parasitic zoonoses which causes serious damage to public health and social development. China is one of the countries most affected by Schistosoma japonicum and an effective vaccine is still needed. In this study, we adopted Tat-mediated protein transduction technology to investigate the impact of different antigen presented approaches on host’s immune response and the potential protection against Schistosoma japonicum infection. Results We successfully constructed the recombinant S. japonicum triosephosphate isomerase, Tat-TPI, as a vaccine candidate. Whether injected with Tat-TPI in foot pad or vaccinated with Tat-TPI in the back subcutaneously for three times, the draining popliteal lymph nodes and spleen both developed a stronger CD8+T response (Tc1) in mice. Not only that, but it also helped CD4+T cells to produce more IFN-γ than TPI immunisation. In addition, it could boost IgG production, especially IgG1 subclass. Most importantly, Tat-TPI immunisation led to the significant smaller area of a single egg granuloma in the livers as compared with TPI-vaccinated or control groups. However, the anti-infection efficiency induced by Tat-TPI was still restricted. Conclusion This study indicated that immunisation with Tat-fused TPI could contribute to enhance CD4+T-cell response and decrease hepatic egg granulomatous area after S. japonicum infection though it did not achieve our expected protection against Schistosoma japonicum infection. The optimal vaccine strategy warrants further research.
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Affiliation(s)
- Wenyue Zhang
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
| | - Xiaofeng Luo
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
| | - Fan Zhang
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
| | - Yuxiao Zhu
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
| | - Bingya Yang
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. .,Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu, 210029, China.
| | - Min Hou
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
| | - Zhipeng Xu
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. .,Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu, 210029, China.
| | - Chuanxin Yu
- Jiangsu Institute of Parasitic Diseases, Wuxi, Jiangsu, 214064, China.
| | - Yingying Chen
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China.
| | - Lin Chen
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. .,Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu, 210029, China.
| | - Minjun Ji
- Department of Pathogen Biology, Nanjing Medical University, Nanjing, Jiangsu, 210029, China. .,Jiangsu Province Key Laboratory of Modern Pathogen Biology, Nanjing, Jiangsu, 210029, China.
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Zimmerer J, Swamy P, Sanghavi P, Wright C, Abdel-Rasoul M, Elzein S, Brutkiewicz R, Bumgardner G. Critical role of NKT cells in posttransplant alloantibody production. Am J Transplant 2014; 14:2491-9. [PMID: 25220596 PMCID: PMC4207222 DOI: 10.1111/ajt.12922] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2014] [Revised: 06/13/2014] [Accepted: 07/01/2014] [Indexed: 01/25/2023]
Abstract
We previously reported that posttransplant alloantibody production in CD8-deficient hosts is IL-4+ CD4+ T cell-dependent and IgG1 isotype-dominant. The current studies investigated the hypothesis that IL-4-producing natural killer T cells (NKT cells) contribute to maximal alloantibody production. To investigate this, alloantibody levels were examined in CD8-deficient WT, CD1d KO and Jα18 KO transplant recipients. We found that the magnitude of IgG1 alloantibody production was critically dependent on the presence of type I NKT cells, which are activated by day 1 posttransplant. Unexpectedly, type I NKT cell contribution to enhanced IgG1 alloantibody levels was interferon-γ-dependent and IL-4-independent. Cognate interactions between type I NKT and B cells alone do not stimulate alloantibody production. Instead, NKT cells appear to enhance maturation of IL-4+ CD4+ T cells. To our knowledge, this is the first report to substantiate a critical role for type I NKT cells in enhancing in vivo antibody production in response to endogenous antigenic stimuli.
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Affiliation(s)
- J.M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - P. Swamy
- Medical Student Research Program, College of Medicine, The Ohio State University, Columbus, OH
| | - P.B. Sanghavi
- Medical Student Research Program, College of Medicine, The Ohio State University, Columbus, OH
| | - C.L. Wright
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - M. Abdel-Rasoul
- Center for Biostatistics, The Ohio State University, Columbus, OH 43221
| | - S.M. Elzein
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
| | - R.R. Brutkiewicz
- Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN
| | - G.L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, and the College of Medicine, The Ohio State University, Columbus, OH
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Zimmerer J, Pham T, Wright C, Tobin K, Sanghavi P, Elzein S, Sanders V, Bumgardner G. Alloprimed CD8(+) T cells regulate alloantibody and eliminate alloprimed B cells through perforin- and FasL-dependent mechanisms. Am J Transplant 2014; 14:295-304. [PMID: 24472191 PMCID: PMC4018729 DOI: 10.1111/ajt.12565] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2013] [Revised: 10/07/2013] [Accepted: 10/27/2013] [Indexed: 01/25/2023]
Abstract
While it is well known that CD4(+) T cells and B cells collaborate for antibody production, our group previously reported that CD8(+) T cells down-regulate alloantibody responses following transplantation. However, the exact mechanism involved in CD8(+) T cell-mediated down-regulation of alloantibody remains unclear. We also reported that alloantibody production is enhanced when either perforin or FasL is deficient in transplant recipients. Here, we report that CD8(+) T cell-deficient transplant recipient mice (high alloantibody producers) exhibit an increased number of primed B cells compared to WT transplant recipients. Furthermore, CD8(+) T cells require FasL, perforin and allospecificity to down-regulate posttransplant alloantibody production. In vivo CD8-mediated clearance of alloprimed B cells was also FasL- and perforin-dependent. In vitro data demonstrated that recipient CD8(+) T cells directly induce apoptosis of alloprimed IgG1(+) B cells in co-culture in an allospecific and MHC class I-dependent fashion. Altogether these data are consistent with the interpretation that CD8(+) T cells down-regulate posttransplant alloantibody production by FasL- and perforin-dependent direct elimination of alloprimed IgG1(+) B cells.
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Affiliation(s)
- J.M. Zimmerer
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - T.A. Pham
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - C.L. Wright
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - K.J. Tobin
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - P.B. Sanghavi
- Medical Student Research Program, College of Medicine, The Ohio State University, Columbus, OH
| | - S.M. Elzein
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
| | - V.M. Sanders
- Department of Molecular Virology, Immunology, and Medical Genetics, The Ohio State University Wexner Medical Center, Columbus, OH
| | - G.L. Bumgardner
- Department of Surgery, Comprehensive Transplant Center, The Ohio State University, Columbus, OH
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Cytotoxic effector function of CD4-independent, CD8(+) T cells is mediated by TNF-α/TNFR. Transplantation 2013; 94:1103-10. [PMID: 23222736 DOI: 10.1097/tp.0b013e318270f3c0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Liver parenchymal cell allografts initiate both CD4-dependent and CD4-independent, CD8(+) T cell-mediated acute rejection pathways. The magnitude of allospecific CD8(+) T cell in vivo cytotoxic effector function is maximal when primed in the presence of CD4(+) T cells. The current studies were conducted to determine if and how CD4(+) T cells might influence cytotoxic effector mechanisms. METHODS Mice were transplanted with allogeneic hepatocytes. In vivo cytotoxicity assays and various gene-deficient recipient mice and target cells were used to determine the development of Fas-, TNF-α-, and perforin-dependent cytotoxic effector mechanisms after transplantation. RESULTS CD8(+) T cells maturing in CD4-sufficient hepatocyte recipients develop multiple (Fas-, TNF-α-, and perforin-mediated) cytotoxic mechanisms. However, CD8(+) T cells, maturing in the absence of CD4(+) T cells, mediate cytotoxicity and transplant rejection that is exclusively TNF-α/TNFR-dependent. To determine the kinetics of CD4-mediated help, CD4(+) T cells were adoptively transferred into CD4-deficient mice at various times posttransplant. The maximal influence of CD4(+) T cells on the magnitude of CD8-mediated in vivo allocytotoxicityf occurs within 48 hours. CONCLUSION The implication of these studies is that interference of CD4(+) T cell function by disease or immunotherapy will have downstream consequences on both the magnitude of allocytotoxicity as well as the cytotoxic effector mechanisms used by allospecific CD8(+) cytolytic T cells.
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