CARDIAC TRANSPLANTATION--IMMUNOLOGIC MODIFICATION

The goal of this proposal is to continue to study methods of immunologic manipulation of the host and of the graft in a rat cardiac model that will avoid long-term immunosuppression of the host and which may have eventual clinical application. It focuses on the evaluation of the effectiveness and mechanisms of induction of immunologic unresponsiveness in the host by deliberate introduction of soluble alloantigens into the thymus of adult rodents and is based on extensive preliminary studies. Induction of tolerance to organ allografts without chronic immunosuppression in rats is possible using intrathymic inoculation of allogeneic resting T-cells or 3M KC1 extracts of such T-cells. We intend to expand on our previous studies and 1) to determine the nature of the peptides necessary for regulation of the immunologic response or clonal deletion by intrathymic injection; 2) to evaluate the events that occur in the thymic microenvironment by in vivo as well as by in vitro correlates to tolerance induction and to determine the timing of such events which appear to be critical; and 3) to study the lymphocyte and peptide migration patterns and cytokine requirements in relation to the development of unresponsiveness. Emphasis will be placed on studying induction of clonal deletion or of anergy in the thymic microenvironment using limiting dilution analysis and appropriate in vitro-in vivo correlates. We expect that with better understanding of the mechanisms involved in induction of immunologic unresponsiveness in the rodent, we will be able to approach the large animal model and eventually clinical trials on a more rationale basis than is possible at this time.