Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice

Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported t...

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Main Authors: James S. Young, Stella H.-W. Khiew, Jinghui Yang, Augustin Vannier, Dengping Yin, Roger Sciammas, Maria-Luisa Alegre, Anita S. Chong
Format: Article
Language:English
Published: Frontiers Media S.A. 2017-09-01
Series:Frontiers in Immunology
Subjects:
Online Access:http://journal.frontiersin.org/article/10.3389/fimmu.2017.01169/full
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author James S. Young
Stella H.-W. Khiew
Jinghui Yang
Jinghui Yang
Augustin Vannier
Dengping Yin
Roger Sciammas
Maria-Luisa Alegre
Anita S. Chong
author_facet James S. Young
Stella H.-W. Khiew
Jinghui Yang
Jinghui Yang
Augustin Vannier
Dengping Yin
Roger Sciammas
Maria-Luisa Alegre
Anita S. Chong
author_sort James S. Young
collection DOAJ
description Clinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.
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spelling doaj.art-3c204d0e424b4717ab46a394bf210d1b2022-12-22T00:20:53ZengFrontiers Media S.A.Frontiers in Immunology1664-32242017-09-01810.3389/fimmu.2017.01169290824Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in MiceJames S. Young0Stella H.-W. Khiew1Jinghui Yang2Jinghui Yang3Augustin Vannier4Dengping Yin5Roger Sciammas6Maria-Luisa Alegre7Anita S. Chong8Department of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United StatesDepartment of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United StatesDepartment of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United StatesDepartment of Organ Transplantation, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai, ChinaDepartment of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United StatesDepartment of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United StatesCenter for Comparative Medicine, University of California, Davis, Davis, CA, United StatesDepartment of Medicine, Section of Rheumatology, The University of Chicago, Chicago, IL, United StatesDepartment of Surgery, Section of Transplantation, The University of Chicago, Chicago, IL, United StatesClinical observations that kidney transplant recipients receiving belatacept who experienced T cell-mediated acute rejection can be successfully treated and subsequently maintained on belatacept-based immunosuppression suggest that belatacept is able to control memory T cells. We recently reported that treatment with CTLA4-Ig from day 6 posttransplantation successfully rescues allografts from acute rejection in a BALB/c to C57BL/6 heart transplant model, in part, by abolishing B cell germinal centers and reducing alloantibody titers. Here, we show that CTLA4-Ig is additionally able to inhibit established T cell responses independently of B cells. CTLA4-Ig inhibited the in vivo cytolytic activity of donor-specific CD8+ T cells, and the production of IFNγ by graft-infiltrating T cells. Delayed CTLA4-Ig treatment did not reduce the numbers of graft-infiltrating T cells nor prevented the accumulation of antigen-experienced donor-specific memory T cells in the spleen. Nevertheless, delayed CTLA4-Ig treatment successfully maintained long-term graft acceptance in the majority of recipients that had experienced a rejection crisis, and enabled the acceptance of secondary BALB/c heart grafts transplanted 30 days after the first transplantation. In summary, we conclude that delayed CTLA4-Ig treatment is able to partially halt ongoing T cell-mediated acute rejection. These findings extend the functional efficacy of CTLA4-Ig therapy to effector T cells and provide an explanation for why CTLA4-Ig-based immunosuppression in the clinic successfully maintains long-term graft survival after T cell-mediated rejection.http://journal.frontiersin.org/article/10.3389/fimmu.2017.01169/fulltransplantationallospecificcostimulatory blockadeCTLA4-IgT lymphocyteheart
spellingShingle James S. Young
Stella H.-W. Khiew
Jinghui Yang
Jinghui Yang
Augustin Vannier
Dengping Yin
Roger Sciammas
Maria-Luisa Alegre
Anita S. Chong
Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice
Frontiers in Immunology
transplantation
allospecific
costimulatory blockade
CTLA4-Ig
T lymphocyte
heart
title Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice
title_full Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice
title_fullStr Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice
title_full_unstemmed Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice
title_short Successful Treatment of T Cell-Mediated Acute Rejection with Delayed CTLA4-Ig in Mice
title_sort successful treatment of t cell mediated acute rejection with delayed ctla4 ig in mice
topic transplantation
allospecific
costimulatory blockade
CTLA4-Ig
T lymphocyte
heart
url http://journal.frontiersin.org/article/10.3389/fimmu.2017.01169/full
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