This proposal is designed to continue to study methods of immunologic manipulation of the graft and of the host in a rat cardiac allograft model that will avoid long-term immunosuppression of the host and which may have clinical application. Special attention will be focused on the induction of specific unresponsiveness in the host by pre-transplant, peritransplant, and posttransplant immunologic modifications with 1) naive or UVB- irradiated lymphocyte subset infusions; 2) pre-transplant intrathymic injection of naive or UVB-irradiated donor lymphoid cells and 3) use of intrasplenic injections of radiolabeled allogeneic gamma irradiated donor lymphocytes as a source of shortlived irradiation in systemic lymphoid irradiation of host. We also wish to continue to modify the organ allografts so as to deplete it of antigen-presenting cells to a maximum degree using agents that may be potentially toxic to the leukocyte/monocyte series. We will continue to study the synergism of such manipulation with peritransplant immunosuppression of the host, especially with Cyclosporin A and/or monoclonal anti-CD4 antibodies. In defining the mechanism of action of the various procedures and induction of donor-specific unresponsiveness in this model, emphasis will be placed on the induction of suppressor-like activity at the cellular and molecular levels and on the abrogation of antigen presentation to develop a better understanding of these processes to permit improvement of these approaches for future clinical applications. The goal of this proposal continues to be to develop a peritransplant host and graft treatment protocols which will result in 1) donor-specific prolonged graft survival; 2) reduction of, or avoidance of, standard immunosuppression after grafting; 3) retention of host immunocompetence to other antigens; and 4) clarification of mechanism of induction of unresponsiveness by alteration of antigen presentation and appropriate conditioning of the host. It is expected that optimal protocols developed in strongly histoincompatible rat allograft models will permit subsequent evaluation in non-human primate models of cardiac allografts and if successful, will be adapted to clinical cardiac transplantation in man.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL014799-18
Application #
3334841
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1977-02-01
Project End
1995-03-31
Budget Start
1991-04-01
Budget End
1992-03-31
Support Year
18
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Columbia University (N.Y.)
Department
Type
Schools of Medicine
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10027
Saborio, D V; Chowdhury, N C; Hardy, M A et al. (1999) Maintenance of acquired thymic tolerance to rat islet allografts by regulatory/suppressor T cells. Transplant Proc 31:897
Saborio, D V; Chowdhury, N C; Jin, M X et al. (1999) Regulatory T cells maintain peripheral tolerance to islet allografts induced by intrathymic injection of MHC class I allopeptides. Cell Transplant 8:375-81
Chowdhury, N C; Saborio, D V; Garrovillo, M et al. (1998) Comparative studies of specific acquired systemic tolerance induced by intrathymic inoculation of a single synthetic Wistar-Furth (RT1U) allo-MHC class I (RT1.AU) peptide or WAG (RT1U)-derived class I peptide. Transplantation 66:1059-66
Rabkin, D G; Stifelman, M D; Birkhoff, J et al. (1998) Early catheter removal decreases incidence of urinary tract infections in renal transplant recipients. Transplant Proc 30:4314-6
Hardy, M A; Eiref, S D; Anastasatos, J (1998) Donor and recipient immunomodulation as an aid for limb transplantation. Transplant Proc 30:2732-6;discussion 2737-8
Oluwole, S F; Chowdhury, N C; Jin, M X et al. (1997) Acquired systemic tolerance to islet allografts induced by intrathymic inoculation of alloantigens--a brief review. Ann Transplant 2:81-5
Chowdhury, N C; Murphy, B; Sayegh, M H et al. (1997) Induction of transplant tolerance by intrathymic inoculation of synthetic MHC class I allopeptides. Transplant Proc 29:1136
Fiedor, P; Jin, M X; Hardy, M A et al. (1997) Induction of tolerance to islet allografts in the high responder rat by intrathymic inoculation of soluble alloantigens. Transplant Proc 29:764
Noizat-Pirenne, F; Greenfeld, J I; Hardy, M A et al. (1996) UVB-irradiation of human bone marrow: potential for donor specific tolerance. J Surg Res 61:267-74
Chowdhury, N C; Murphy, B; Sayegh, M H et al. (1996) Acquired systemic tolerance to rat cardiac allografts induced by intrathymic inoculation of synthetic polymorphic MHC class I allopeptides. Transplantation 62:1878-82

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