Delayed Cytotoxic T Lymphocyte–Associated Protein 4–Immunoglobulin Treatment Reverses Ongoing Alloantibody Responses and Rescues Allografts From Acute Rejection

J. S. Young, J. Chen, M. L. Miller, V. Vu, C. Tian, J. J. Moon, M. L. Alegre, Roger Sciammas, A. S. Chong

Research output: Contribution to journalArticle

24 Scopus citations

Abstract

Antibody-mediated rejection has emerged as the leading cause of late graft loss in kidney transplant recipients, and inhibition of donor-specific antibody production should lead to improved transplant outcomes. The fusion protein cytotoxic T lymphocyte–associated protein 4–immunoglobulin (CTLA4-Ig) blocks T cell activation and consequently inhibits T-dependent B cell antibody production, and the current paradigm is that CTLA4-Ig is effective with naïve T cells and less so with activated or memory T cells. In this study, we used a mouse model of allosensitization to investigate the efficacy of continuous CTLA4-Ig treatment, initiated 7 or 14 days after sensitization, for inhibiting ongoing allospecific B cell responses. Delayed treatment with CTLA4-Ig collapsed the allospecific germinal center B cell response and inhibited alloantibody production. Using adoptively transferred T cell receptor transgenic T cells and a novel approach to track endogenous graft-specific T cells, we demonstrate that delayed CTLA4-Ig minimally inhibited graft-specific CD4+ and T follicular helper responses. Remarkably, delaying CTLA4-Ig until day 6 after transplantation in a fully mismatched heart transplant model inhibited alloantibody production and prevented acute rejection, whereas transferred hyperimmune sera reversed the effects of delayed CTLA4-Ig. Collectively, our studies revealed the unexpected efficacy of CTLA4-Ig for inhibiting ongoing B cell responses even when the graft-specific T cell response was robustly established.

Original languageEnglish (US)
Pages (from-to)2312-2323
Number of pages12
JournalAmerican Journal of Transplantation
Volume16
Issue number8
DOIs
StatePublished - Aug 1 2016
Externally publishedYes

Keywords

  • alloantibody
  • animal models: murine
  • B cell biology
  • basic (laboratory) research/science
  • fusion proteins and monoclonal antibodies: belatacept
  • immunobiology
  • immunosuppressant
  • immunosuppression/immune modulation
  • immunosuppressive regimens
  • organ transplantation in general
  • rescue

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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