The induction of transplantation unresponsiveness remains an elusive goal. Clinical applications of organ transplantation have only been possible due to the chronic use of a variety of immunosuppressive agents, which not only incompletely control allograft rejection, but also confer significant patient morbidity. This application proposes to test the hypothesis that a combined regimen of 3M KCl-extracted histocompatibility antigen (HAg), which stimulates specific T-cell suppressor functions, and a brief course of cyclosporine (CsA), a cyclic endecapeptide of novel structure which depresses T-lymphocyte helper functions, induces long-term, donor-specific allograft survival. Intravenous injection of 5 mg HAg either on day -1 (or +1) combined with 10 mg/kg po CsA on three days (-1, 0, +1) prolongs rat renal allografts transplanted across an RT-1 barrier on day 0 from 7.9 to 26.8 days. When HAg is combined with 9 doses of CsA (days -1, 0, +1, 7, 8, 9; 14, 15, 16), 50% of hosts were permanently unresponsive not only to renal allografts, but also to challenge donor-type, but not third-party, skin grafts applied at 80 days. Prolonged survival was transferred to normal syngeneic hosts with purified OX8+ cells. The proposed studies will translate the rat model to more stringent models of mouse H-2 incompatibility and outbred mongrel dogs. In addition, immunologic aspects of suppressor cell function in the rat model will be dissected in order to discover variables that optimize the induction of unresponsiveness, including purification, amplification and characterization of the rat suppressor cell (and its mouse analogue if such can be generated), as well as identifying the class nature of histocompatibility antigens inducing the phenomenon. If the experiments identify a regimen capable of inducing consistently prolonged survival in these stringent models, it will provide the foundation for immediate preclinical tests using inbred beagle dogs, and subhuman primates. Because this conditioning regimen utilizes a brief time frame consistent with the strictures of human cadaveric donor organ transplants, it proffers the opportunity to actively induce unresponsiveness in patients, thereby mitigating the need for chronic immunosuppression.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI022664-01
Application #
3134083
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1985-07-01
Project End
1988-06-30
Budget Start
1985-07-01
Budget End
1986-06-30
Support Year
1
Fiscal Year
1985
Total Cost
Indirect Cost
Name
University of Texas Health Science Center Houston
Department
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77225
Okamoto, M; Stepkowski, S M; Wang, M et al. (2000) Use of allochimeric proteins to mitigate graft-versus-host and host-versus-graft immune responses to rat small bowel allografts. Transplantation 70:1060-7
Boyle, M J; Baghdassarian, V; Stepkowski, S M et al. (1998) Intrasplenic liver parenchymal cells in conjunction with low-dose rapamycin and cyclosporine induce a unique and specific prolongation of rat cardiac and small bowel allograft survival. Cell Transplant 7:247-56
Wang, M; Stepkowski, S M; Yu, J et al. (1997) Localization of cryptic tolerogenic epitopes in the alpha1-helical region of the RT1.Au alloantigen. Transplantation 63:1373-9
Stepkowski, S M; Wang, M; Langowski, J et al. (1997) Localization of tolerogenic epitopes in the alpha 1 helical region of the rat class I major histocompatibility complex molecule. Transplant Proc 29:1663-4
Wang, M; Stepkowski, S M; Tian, L et al. (1997) Nucleotide sequences of rat cDNA clones coding heavy chain class I major histocompatibility complex proteins. Transplant Proc 29:1661-2
Wang, M; Stepkowski, S M; Hebert, J S et al. (1996) Nucleotide sequences of three H-2K and three H-2D complementary DNA clones coding mouse class I MHC heavy chain proteins. Ann Transplant 1:26-31
Wang, M; Stepkowski, S M; Wang, M E et al. (1996) Induction of specific allograft immunity by soluble class I MHC heavy chain protein produced in a baculovirus expression system. Transplantation 61:448-57
He, G; Wang, M; Xu, H et al. (1996) Impact of different forms of recipient antigen and different routes of antigen administration in donor pretreatment for preventing graft-versus-host disease in rat small bowel transplantation. Transplant Proc 28:2469
Ghobrial, R R; Hamashima, T; Wang, M E et al. (1996) Induction of transplantation tolerance by chimeric donor/recipient class I RT1.Aa molecules. Transplantation 62:1002-10
Hamashima, T; Stepkowski, S M; Chou, T C et al. (1995) Synergistic interaction of 3 M KCl-extracted donor antigens (e-HAg) with cyclosporine or cyclosporine/sirolimus for prolongation of rat heart allograft survival. Transpl Immunol 3:335-41

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