CD28-B7 T cell costimulatory blockade by CTLA4Ig in sensitized rat recipients: induction of transplantation tolerance in association with depressed cell-mediated and humoral immune responses.

We tested the effects of blocking CD28-B7 T cell costimulation by using CTLA4Ig in an established transplantation model in which LBNF1 cardiac allografts are rejected in an accelerated manner (<36 h) by LEW rats presensitized with Brown-Norway skin grafts. Treatment with CTLA4Ig with or without donor alloantigen in the sensitization phase (between skin and cardiac engraftment) minimally delayed accelerated rejection. However, adjunctive infusion of CTLA4Ig and donor alloantigen in the effector phase (after cardiac engraftment) resulted in long term graft survival and donor-specific tolerance in 30 to 50% of the recipients. The mutant form of CTLA4Ig, which blocks B7-1 but not B7-2, was ineffective. The tolerant state was accompanied by reduction of cell-mediated (MLR/CTL) responses and depression of humoral (circulating IgM/IgG allo-Abs) alloreactivity in vivo. Hence, the binding of CD28 on T cells to both CD80 and CD86 ligands represents a crucial initial costimulatory step leading to accelerated graft rejection. CTLA4Ig-mediated early blockade of the CD28 signaling pathway combined with transfusion of donor cells in the perioperative period interrupts sensitization and may produce transplantation tolerance. This regimen inhibits T cell costimulation and activation to provide help to CD8+ cytotoxic T and B cells, perhaps, via CTLA4Ig-induced clonal anergy or deletion.