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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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University of Pennsylvania
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Naji, A (1996) Induction of tolerance by intrathymic inoculation of alloantigen. Curr Opin Immunol 8:704-9
Campos, L; Deli, B C; Kern, J H et al. (1995) Survival of MHC deficient mouse heterotopic cardiac allografts and xenografts. Transplant Proc 27:254-5
Campos, L; Naji, A; Deli, B C et al. (1995) Survival of MHC-deficient mouse heterotopic cardiac allografts. Transplantation 59:187-91
Mayo, G L; Posselt, A M; Barker, C F et al. (1994) Prolongation of survival of donor-strain islet xenografts (rat-->mouse) by intrathymic inoculation of xenogeneic islet and bone marrow cells. Transplantation 58:107-9
Markmann, J F; Campos, L; Bhandoola, A et al. (1994) Genetically engineered grafts to study xenoimmunity: a role for indirect antigen presentation in the destruction of major histocompatibility complex antigen deficient xenografts. Surgery 116:242-8;discussion 248-9
Mayo, G L; Posselt, A M; Campos, L et al. (1994) Intrathymic transplantation promotes survival of islet xenografts (rat-->mouse). Transplant Proc 26:758
Campos, L; Posselt, A M; Deli, B C et al. (1994) The failure of intrathymic transplantation of nonimmunogenic islet allografts to promote induction of donor-specific unresponsiveness. Transplantation 57:950-3
Campos, L; Alfrey, E J; Posselt, A M et al. (1993) Intrathymic inoculation of donor cells promotes survival of rat orthotopic liver allografts. Transplant Proc 25:488-9
Odorico, J S; Barker, C F; Markmann, J F et al. (1993) Prolonged survival of rat cardiac allografts after intrathymic inoculation of donor thymocytes. Transplant Proc 25:295-6
Posselt, A M; Barker, C F; Friedman, A L et al. (1993) Intrathymic inoculation of islets at birth prevents autoimmune diabetes and pancreatic insulitis in the BB rat. Transplant Proc 25:301-2

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