The overall goal is to determine the feasibility of inducing specific allograft tolerance by employing a novel approach that involves transplantation of allogeneic cells to the thymus. Primary attention will be devoted to further investigations of the applicants' findings that rat pancreatic islet allografts transplanted to the thymus are not rejected and, surprisingly also promote successful engraftment and survival of donor strain grafts in extrathymic sites. Studies are proposed to first characterize the immunologically privileged status of the thymus. In addition, a variety of in vivo and in vitro tests in both murine and rat systems will be aimed at examining the mechanisms by which persistence of allogeneic cells in the thymus leads to donor specific unresponsiveness to extrathymic allografts. The applicability of the intrathymic inoculation as an approach for transplantation of nonislet tissues will be assessed using several endocrine and nonendocrine cellular grafts, including cells with known tolerogenic potential (bone marrow, thymic epithelial cells, dendritic cells). The ability of the thymus to support normal physiologic function of these tissues, as well as their capacity to induce peripheral unresponsiveness to extrathymic transplants will be determined.
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