Successful treatment of T cell-mediated acute rejection with delayed CTLA4-Ig in mice

James S. Young, Stella H.W. Khiew, Jinghui Yang, Augustin Vannier, Dengping Yin, Roger Sciammas, Maria Luisa Alegre, Anita S. Chong

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

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.

Original languageEnglish (US)
Article number1169
JournalFrontiers in Immunology
Volume8
Issue numberSEP
DOIs
StatePublished - Sep 20 2017

Keywords

  • Allospecific
  • Costimulatory blockade
  • CTLA4-Ig
  • Heart
  • Memory
  • Sensitization
  • T lymphocyte
  • Transplantation

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Successful treatment of T cell-mediated acute rejection with delayed CTLA4-Ig in mice'. Together they form a unique fingerprint.

  • Cite this

    Young, J. S., Khiew, S. H. W., Yang, J., Vannier, A., Yin, D., Sciammas, R., Alegre, M. L., & Chong, A. S. (2017). Successful treatment of T cell-mediated acute rejection with delayed CTLA4-Ig in mice. Frontiers in Immunology, 8(SEP), [1169]. https://doi.org/10.3389/fimmu.2017.01169