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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL057229-01A1
Application #
2398225
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1997-09-01
Project End
2001-08-31
Budget Start
1997-09-01
Budget End
1998-08-31
Support Year
1
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Surgery
Type
Schools of Medicine
DUNS #
167204994
City
New York
State
NY
Country
United States
Zip Code
10032
Oluwole, Soji F; Oluwole, Olakunle O; Adeyeri, Ayotunde O et al. (2004) New strategies in immune tolerance induction. Cell Biochem Biophys 40:27-48
Oluwole, Olakunle O; DePaz, Hector A; Adeyeri, Ayotunde et al. (2003) Role of CD41CD251 regulatory T cells from naive host thymus in the induction of acquired transplant tolerance by immunization with allo-major histocompatibility complex peptide. Transplantation 75:1136-42
Oluwole, Soji F; Oluwole, Olakunle O; DePaz, Hector A et al. (2003) CD4+CD25+ regulatory T cells mediate acquired transplant tolerance. Transpl Immunol 11:287-93
DePaz, Hector A; Oluwole, Olakunle O; Adeyeri, Ayotunde O et al. (2003) Immature rat myeloid dendritic cells generated in low-dose granulocyte macrophage-colony stimulating factor prolong donor-specific rat cardiac allograft survival. Transplantation 75:521-8
Fawwaz, Rashid A; Oluwole, Olakunle O; DePaz, Hector A et al. (2002) Peritransplant streptavidin recipient treatment prolongs rat cardiac allograft survival. Transplantation 73:1954-6
Garrovillo, M; Ali, A; Depaz, H A et al. (2001) Induction of transplant tolerance with immunodominant allopeptide-pulsed host lymphoid and myeloid dendritic cells. Am J Transplant 1:129-37
Gopinathan, R; DePaz, H A; Oluwole, O O et al. (2001) Mechanisms of acquired tolerance induced by adoptive transfer of MHC-specific alloreactive T cells: effector T cells migrate to the thymus. Transplant Proc 33:92
Ali, A O; Garrovillo, M; Oluwole, O O et al. (2001) Induction of acquired tolerance to cardiac allografts by adoptive transfer of in vivo allopeptide activated T cells. Transplant Proc 33:97
Oluwole, O O; Depaz, H A; Gopinathan, R et al. (2001) Indirect allorecognition in acquired thymic tolerance: induction of donor-specific permanent acceptance of rat islets by adoptive transfer of allopeptide-pulsed host myeloid and thymic dendritic cells. Diabetes 50:1546-52
Oluwole, O O; DePaz, H A; Gopinathan, R et al. (2001) Thymic recognition of AlloMHC peptide-primed alloreactive T cells induces specific unresponsiveness to islets. Transplant Proc 33:96

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