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

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.