Rejection remains a potent threat to the long term success of organ transplants and significant morbidity is associated with even the best of modern immunosuppressive agents. The best hope for improving allograft survival, and particularly for preventing chronic rejection, is the induction of a state of donor-specific tolerance. The overall goal of this project is to explore the mechanism(s) of allograft tolerance which follows inoculation of the donor alloantigen directly into the thymus. Previous studies by ourselves and others have confirmed the efficacy of intrathymic inocula of endocrine or lymphohematopoietic cells to promote acceptance of subsequent extrathymic cellular or organ allografts in rodents. The first specific aim of this project is to examine whether deletion is the primary mechanism responsible for thymus-mediated tolerance. By utilizing several murine models with well-defined alloantigenic expressions, we will employ immune repertoire analysis of Vbeta-bearing T cells to explore clonal deletion as the basis for intrathymic tolerance. The second specific aim of this application is to assess the roles of the counterregulatory cytokine network as the mechanism of active clonotypic suppression responsible for the induction of intrathymic tolerance. Novel MHC knockout mice will be utilized to assess the role of the host lymphoid cells to promote specific cytokine profiles important in the induction and maintenance of tolerance following intrathymic inoculation with donor alloantigen.
In specific aim 3 we will utilize a preclinical model of SCID mice reconstituted with human lymphohematopoietic and thymus grafts to simulate the human immune system. SCID-hu constructs will be used to assess the ability of the human thymus to nurture autografts and allografts of pancreatic islets and to reverse experimental diabetes. The impact of the residence of allogeneic islets in the human thymus on the peripheral T cell repertoire will be assessed as well as the possible induction of specific tolerance to extrathymic islets from the same donor. Intrathymic inocula of allogeneic lymphoid cells will also be tested as a tolerogen to promote donor-specific unresponsiveness to extrathymic islet allografts. Collectively, the present application proposes to delineate the mechanism(s) of acquired thymus-mediated immune tolerance and to utilize this information to optimize its potential utility in man.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK044309-04A1
Application #
2143697
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1991-08-01
Project End
1999-03-31
Budget Start
1995-04-27
Budget End
1996-03-31
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Surgery
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
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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