Long-term acceptance of major histocompatibility complex mismatched cardiac allografts induced by CTLA4Ig plus donor-specific transfusion.

TLDR

Allograft rejection depends on T‑cell activation requiring both TCR engagement and CD28 costimulation, and CTLA4Ig can block CD28–B7 interactions to inhibit antigen‑specific immune responses, prolonging graft survival in rats. The study aims to determine whether combining donor‑specific transfusion with CTLA4Ig can achieve long‑term cardiac allograft survival. CTLA4Ig, a soluble fusion protein that blocks CD28–B7 costimulation, was employed to suppress T‑cell activation. Combining donor‑specific transfusion with a single post‑transplant dose of CTLA4Ig resulted in long‑term (>60 days) cardiac allograft survival, delayed rejection of donor‑type skin, tolerance of second grafts, and suggests clinical applicability for human transplantation.

Abstract

Allograft rejection is a T cell-dependent process. Productive T cell activation by antigen requires antigen engagement of the T cell receptor as well as costimulatory signals delivered through other T cell surface molecules such as CD28. Engagement of CD28 by its natural ligand B7 can be blocked using a soluble recombinant fusion protein, CTLA4Ig. Administration of CTLA4Ig blocks antigen-specific immune responses in vitro and in vivo, and we have shown that treatment of rats with a 7-d course of CTLA4Ig at the time of transplantation leads to prolonged survival of cardiac allografts (median 30 d), although most grafts are eventually rejected. Here, we have explored additional strategies employing CTLA4Ig in order to achieve long-term allograft survival. Our data indicate that donor-specific transfusion (DST) plus CTLA4Ig can provide effective antigen-specific immunosuppression. When DST is administered at the time of transplantation followed by a single dose of CTLA4Ig 2 d later, all animals had long-term graft survival (> 60 d). These animals had delayed responses to donor-type skin transplants, compared with normal rejection responses to third-party skin transplants. Furthermore, donor-matched second cardiac allografts were well tolerated with minimal histologic evidence of rejection. These data indicate that peritransplant use of DST followed by subsequent treatment with CTLA4Ig can induce prolonged, often indefinite, cardiac allograft acceptance. These results may be clinically applicable for cadaveric organ and tissue transplantation in humans.