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      Relative Frequencies of Alloantigen-Specific Helper CD4 T Cells and B Cells Determine Mode of Antibody-Mediated Allograft Rejection

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          Abstract

          Humoral alloimmunity is now recognized as a major determinant of transplant outcome. MHC glycoprotein is considered a typical T-dependent antigen, but the nature of the T cell alloresponse that underpins alloantibody generation remains poorly understood. Here, we examine how the relative frequencies of alloantigen-specific B cells and helper CD4 T cells influence the humoral alloimmune response and how this relates to antibody-mediated rejection (AMR). An MHC-mismatched murine model of cardiac AMR was developed, in which T cell help for alloantibody responses in T cell deficient ( Tcrbd −/−) C57BL/6 recipients against donor H-2K d MHC class I alloantigen was provided by adoptively transferred “TCR75” CD4 T cells that recognize processed H-2K d allopeptide via the indirect-pathway. Transfer of large numbers (5 × 10 5) of TCR75 CD4 T cells was associated with rapid development of robust class-switched anti-H-2K d humoral alloimmunity and BALB/c heart grafts were rejected promptly (MST 9 days). Grafts were not rejected in T and B cell deficient Rag2 −/− recipients that were reconstituted with TCR75 CD4 T cells or in control (non-reconstituted) Tcrbd −/− recipients, suggesting that the transferred TCR75 CD4 T cells were mediating graft rejection principally by providing help for effector alloantibody responses. In support, acutely rejecting BALB/c heart grafts exhibited hallmark features of acute AMR, with widespread complement C4d deposition, whereas cellular rejection was not evident. In addition, passive transfer of immune serum from rejecting mice to Rag2 −/− recipients resulted in eventual BALB/c heart allograft rejection (MST 20 days). Despite being long-lived, the alloantibody responses observed at rejection of the BALB/c heart grafts were predominantly generated by extrafollicular foci: splenic germinal center (GC) activity had not yet developed; IgG secreting cells were confined to the splenic red pulp and bridging channels; and, most convincingly, rapid graft rejection still occurred when recipients were reconstituted with similar numbers of Sh2d1a −/− TCR75 CD4 T cells that are genetically incapable of providing T follicular helper cell function for generating GC alloimmunity. Similarly, alloantibody responses generated in Tcrbd −/− recipients reconstituted with smaller number of wild-type TCR75 CD4 T cells (10 3), although long-lasting, did not have a discernible extrafollicular component, and grafts were rejected much more slowly (MST 50 days). By modeling antibody responses to Hen Egg Lysozyme protein, we confirm that a high ratio of antigen-specific helper T cells to B cells favors development of the extrafollicular response, whereas GC activity is favored by a relatively high ratio of B cells. In summary, a relative abundance of helper CD4 T cells favors development of strong extrafollicular alloantibody responses that mediate acute humoral rejection, without requirement for GC activity.

          This work is composed of two parts, of which this is Part I. Please read also Part II: Chhabra et al., 2019.

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          Most cited references41

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          The 2013 International Society for Heart and Lung Transplantation Working Formulation for the standardization of nomenclature in the pathologic diagnosis of antibody-mediated rejection in heart transplantation.

          During the last 25 years, antibody-mediated rejection of the cardiac allograft has evolved from a relatively obscure concept to a recognized clinical complication in the management of heart transplant patients. Herein we report the consensus findings from a series of meetings held between 2010-2012 to develop a Working Formulation for the pathologic diagnosis, grading, and reporting of cardiac antibody-mediated rejection. The diagnostic criteria for its morphologic and immunopathologic components are enumerated, illustrated, and described in detail. Numerous challenges and unresolved clinical, immunologic, and pathologic questions remain to which a Working Formulation may facilitate answers.
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            B Cell Receptor–independent Stimuli Trigger Immunoglobulin (Ig) Class Switch Recombination and Production of IgG Autoantibodies by Anergic Self-Reactive B Cells

            In both humans and animals, immunoglobulin (Ig)G autoantibodies are less frequent but more pathogenic than IgM autoantibodies, suggesting that controls over Ig isotype switching are required to reinforce B cell self-tolerance. We have used gene targeting to produce mice in which hen egg lysozyme (HEL)-specific B cells can switch to all Ig isotypes (SWHEL mice). When crossed with soluble HEL transgenic (Tg) mice, self-reactive SWHEL B cells became anergic. However, in contrast to anergic B cells from the original nonswitching anti-HEL × soluble HEL double Tg model, self-reactive SWHEL B cells also displayed an immature phenotype, reduced lifespan, and exclusion from the splenic follicle. These differences were not related to their ability to Ig class switch, but instead to competition with non-HEL–binding B cells generated by VH gene replacement in SWHEL mice. When activated in vitro with B cell receptor (BCR)-independent stimuli such as anti-CD40 monoclonal antibody plus interleukin 4 or lipopolysaccharide (LPS), anergic SWHEL double Tg B cells proliferated and produced IgG anti-HEL antibodies as efficiently as naive HEL-binding B cells from SWHEL Ig Tg mice. These results demonstrate that no intrinsic constraints to isotype switching exist in anergic self-reactive B cells. Instead, production of IgG autoantibodies is prevented by separate controls that reduce the likelihood of anergic B cells encountering BCR-independent stimuli. That bacteria-derived LPS could circumvent these controls may explain the well-known association between autoantibody-mediated diseases and episodes of systemic infection.
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              Antibody-mediated rejection across solid organ transplants: manifestations, mechanisms, and therapies.

              Solid organ transplantation is a curative therapy for hundreds of thousands of patients with end-stage organ failure. However, long-term outcomes have not improved, and nearly half of transplant recipients will lose their allografts by 10 years after transplant. One of the major challenges facing clinical transplantation is antibody-mediated rejection (AMR) caused by anti-donor HLA antibodies. AMR is highly associated with graft loss, but unfortunately there are few efficacious therapies to prevent and reverse AMR. This Review describes the clinical and histological manifestations of AMR, and discusses the immunopathological mechanisms contributing to antibody-mediated allograft injury as well as current and emerging therapies.
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                Author and article information

                Contributors
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                22 January 2019
                2018
                : 9
                : 3039
                Affiliations
                [1] 1School of Clinical Medicine, University of Cambridge , Cambridge, United Kingdom
                [2] 2Department of Pathology, Papworth Hospital , Papworth Everard, United Kingdom
                [3] 3Histocompatibility and Immunogenetics Laboratory, Cambridge University Hospitals NHS Foundation Trust , Cambridge, United Kingdom
                [4] 4Laboratory of Lymphocyte Signalling and Development, Babraham Institute , Cambridge, United Kingdom
                [5] 5Division of Surgery and Interventional Sciences, University College London , London, United Kingdom
                [6] 6Centre for Transplantation, Department of Renal Medicine, University College London , London, United Kingdom
                [7] 7Institute of Immunity and Transplantation, University College London , London, United Kingdom
                Author notes

                Edited by: Antoine Toubert, Paris Diderot University, France

                Reviewed by: Luiza Guilherme, University of São Paulo, Brazil; Frans Claas, Leiden University, Netherlands

                *Correspondence: Reza Motallebzadeh r.motallebzadeh@ 123456ucl.ac.uk
                Gavin J. Pettigrew gjp25@ 123456cam.ac.uk

                This article was submitted to Alloimmunity and Transplantation, a section of the journal Frontiers in Immunology

                †These authors have contributed equally to this work

                Article
                10.3389/fimmu.2018.03039
                6357941
                30740108
                48f7d31c-f2d4-41ef-868b-b8d583ae9124
                Copyright © 2019 Alsughayyir, Chhabra, Qureshi, Mallik, Ali, Gamper, Moseley, Peacock, Kosmoliaptsis, Goddard, Linterman, Motallebzadeh and Pettigrew.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 October 2018
                : 07 December 2018
                Page count
                Figures: 7, Tables: 0, Equations: 0, References: 61, Pages: 15, Words: 9412
                Categories
                Immunology
                Original Research

                Immunology
                allograft,humoral alloimmunity,germinal center (gc),extrafollicular b cell response,transplantation,vasculopathy

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