This proposal is designed to continue to study methods of immunologic manipulation of the graft and of the host in a rat cardiac allograft model that will avoid long-term immunosuppression of the host and which may have clinical application. Special attention will be focused on the induction of specific unresponsiveness in the host by pre-transplant, peritransplant, and posttransplant immunologic modifications with 1) naive or UVB- irradiated lymphocyte subset infusions; 2) pre-transplant intrathymic injection of naive or UVB-irradiated donor lymphoid cells and 3) use of intrasplenic injections of radiolabeled allogeneic gamma irradiated donor lymphocytes as a source of shortlived irradiation in systemic lymphoid irradiation of host. We also wish to continue to modify the organ allografts so as to deplete it of antigen-presenting cells to a maximum degree using agents that may be potentially toxic to the leukocyte/monocyte series. We will continue to study the synergism of such manipulation with peritransplant immunosuppression of the host, especially with Cyclosporin A and/or monoclonal anti-CD4 antibodies. In defining the mechanism of action of the various procedures and induction of donor-specific unresponsiveness in this model, emphasis will be placed on the induction of suppressor-like activity at the cellular and molecular levels and on the abrogation of antigen presentation to develop a better understanding of these processes to permit improvement of these approaches for future clinical applications. The goal of this proposal continues to be to develop a peritransplant host and graft treatment protocols which will result in 1) donor-specific prolonged graft survival; 2) reduction of, or avoidance of, standard immunosuppression after grafting; 3) retention of host immunocompetence to other antigens; and 4) clarification of mechanism of induction of unresponsiveness by alteration of antigen presentation and appropriate conditioning of the host. It is expected that optimal protocols developed in strongly histoincompatible rat allograft models will permit subsequent evaluation in non-human primate models of cardiac allografts and if successful, will be adapted to clinical cardiac transplantation in man.
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