Deleterious effect of CTLA4-Ig on a treg-dependent transplant model

L. V. Riella, T. Liu, J. Yang, S. Chock, T. Shimizu, B. Mfarrej, I. Batal, X. Xiao, M. H. Sayegh, Anil Chandraker

Research output: Contribution to journalArticlepeer-review

88 Scopus citations

Abstract

Blockade of the B7:CD28 costimulatory pathway has emerged as a promising therapy to prevent allograft rejection. However, results from the belatacept phase III clinical trial demonstrated a higher rejection rate when compared to cyclosporine, raising concern about potential deleterious effects of this agent. In this study, we investigated the consequences of B7:CD28 blockade by hCTLA4Ig on regulator T cell (Treg) generation in differentmajor histocompatibility complex (MHC)mismatch transplant models. Administration of hCTLA4Ig significantly decreased the amount of Tregs in B6 WT animals and this effect was predominant in thymus-induced Tregs (Helios+). Although hCTLA4Ig prevented rejection in a fully allogeneic mismatch model, it accelerated rejection in a MHC class-II mismatch model (MST = 26, p < 0.0001), in which long-term allograft survival is dependent on Tregs. This accelerated rejection was associated with a marked reduction in thymus-induced Tregs and led to a higher effector/ regulatory T-cell ratio in secondary lymphoid organs and in the allograft. This study confirms the importance of the B7:CD28 pathway in Treg homeostasis in an in vivo transplant model and suggests that hCTLA4Ig therapymay be deleterious in circumstances where engraftment is dependent on Tregs.

Original languageEnglish (US)
Pages (from-to)846-855
Number of pages10
JournalAmerican Journal of Transplantation
Volume12
Issue number4
DOIs
StatePublished - Apr 2012

Keywords

  • Costimulation
  • MHC class II
  • Mice
  • Regulatory T cells
  • Rejection

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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