The goal of this proposal is to study methods of immunologic manipulation of the host in a rat cardiac allograft model that will avoid long-term recipient immunosuppression and which may have eventual clinical application. The proposed study focuses on the evaluation of the effectiveness and mechanisms of immunologic unresponsiveness to cardiac allografts induced by the deliberate introduction of well-defined synthetic MHC allopeptides into the thymus of adult rodents. This is based on the hypothesis that tolerance of self antigens occurs because all T-cells, including those that express receptors for self antigens, undergo deletion by apoptosis or anergy whenever they encounter self or non-self antigens during their ontogeny in the thymus and that the development of central tolerance depends on the appropriate presentation of tolerizing antigen (tolerogen) to the developing thymocytes. The outlined experiments are based on extensive preliminary studies using intrathymic (IT) inoculation of allogeneic resting T-cells or 3M KCL extracts of T-cells to induce specific unresponsiveness in the rat cardiac allograft model. We intend to expand our preliminary studies to the use of IT inoculation of synthetic MHC class I and II peptides either alone or combined with a short course of immunosuppression in the induction of donor-specific tolerance to rat cardiac allografts. To define the underlying mechanisms of antigen-specific tolerance in this model, the investigators plan to study 1) the indirect pathway of allorecognition which may play the predominant role in thymic tolerance; 2) clonal deletion or anergy of donor-reactive T-cell precursors; and 3) the cytokine changes occurring in the thymus required for the development of acquired thymic tolerance. They expect that with better understanding of the mechanisms of the in vivo effects of synthetic polymorphic MHC peptides in experimental models, they will be able to approach the large animal model and eventually clinical trials on a more rational basis than is possible at this time.
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