CD28-B7 T-CELL COSTIMULATORY BLOCKADE POTENTIATES THE EFFECTS OF INTRATHYMIC IMMUNOMODULATION IN SENSITIZED GRAFT RECIPIENTS

Background Peripheral and central immune mechanisms contribute to the induction of tolerance in acute rejection rodent transplant models aft er systemic administration of CTLA4Ig and intrathymic infusion of dono r alloantigen, respectively, We have investigated the effects of CTLA4 Ig-induced blockade of CD28-B7 T-cell co-stimulation in conjunction wi th intrathymic immunomodulation on cellular and humoral immune respons es leading to accelerated rejection of cardiac allografts in presensit ized rats. Methods and Results. Lewis rats were challenged with Wistar -Furth (WF) skin transplants, followed 7 days later by transplantation of WF hearts. These cardiac allografts were rejected in a fulminant m anner in <24 hr. A single infusion of human CTLA4Ig (0.5 mg/rat i.v.) at the time of cardiac engraftment (day 0) did not affect accelerated rejection. Intrathymic injection of WF Spleen cells (2x10(7)) at the t ime of skin transplantation (day -7) abrogated <24-hr rejection and ex tended cardiac allograft survival to 6.6+/-0.6 days, Moreover, intrath ymic host immunomodulation combined with administration of human CTLA4 Ig (days 0-14, every other day) extended cardiac allograft survival sy nergistically to 27.7+/-7.5 days, and immunomodulation combined with m urine CTLA4Ig extended survival to >42.5+/-4.8 days, The prolongation of allograft survival required the blockade of both B7-1 and B7-2 liga nds and was accompanied by reduction of host proliferative responses ( mixed lymphocyte response) and depression of anti-donor cytotoxic T-ce ll generation/function (lymphocyte-mediated cytotoxicity). CTLA4Ig the rapy did not affect the strong systemic IgM and IgG alloantibody respo nse seen otherwise after intrathymic immunomodulation. Conclusion. CTL A4Ig enhances the effects of intrathymic donor-type cell infusion in s ensitized rat recipients of cardiac allografts, indicating that ''peri pheral'' blockade of CD28-B7 T-cell co-stimulation synergizes with the ''central'' immunosuppressive effects of intrathymic immunomodulation .