Administration of donor antigen to adult hosts conditioned by immunosuppressive therapy, represents one strategy to produce central immunologic tolerance, leading to host acceptance of foreign transplants. In contrast to their cell-borne counterparts, extracted histocompatibility antigens (e-HAg) proffer not only non-replicating materials bearing a relatively limited array of disparate determinants, but also a soluble state that may display uniquely exposed native, or chemically manipulated artificial, epitopes facilitating tolerance induction. Initial studies revealed the combination of peri-operative therapy with 3M KC1 BUF e- HAg and CsA (10mg/kg/day) to prolong the survival of WFu rat renal, cardiac and pancreatic islet grafts (major plus minor histocompatibility differences), as well as mongrel canine kidney transplants. Alternatively, pre-transplant conditioning with 1600 R total lymphoid irradiation (TLI) followed by e-HAg prolonged rat heart graft survival. On the one hand, the proposed studies seek to improve the e-HAg stimulus by purification of active epitopes, including separation of Class I versus Class II major histocompatibility complex determinants, and by optimization of the route, dose, form and infusion technique. On the other hand, these studies dissect the immunologic effects of e-HAg therapy combined with either CsA or TLI, using limiting dilution analysis to assess precursor frequency of helper, cytotoxic and suppressor T-lymphocyte subpopulations at serial times starting pre-and continuing to 180 days post-transplant. To reveal the target of their action, e-HAg induced suppressor cells are panned on cellular monolayers of or stimulated in proliferation assays with antigen- or idiotype-specific markers. Based upon initial studies showing e-HAg triggers specific suppressor cells, these elements will be cloned, in order to dissect their mechanism of action, specificity, and in vivo and in vitro potency. Finally, the proposed experiments analyze the effects of new immunosuppressive modalities, namely monoclonal rat anti-delta-interferon antibody and continuous intra-arterial CsA infusion, both of which were discovered during the initial grant period, on allograft H-antigen expression, suppressor cell induction, and efferent protection against attack by effector lymphocytes. These studies may provide a foundation for application of e-HAg with selective immunosuppressive adjuncts in preclinical tests, and eventually for clinical organ transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI022664-05
Application #
3134089
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Project Start
1987-03-20
Project End
1993-06-30
Budget Start
1989-07-01
Budget End
1990-06-30
Support Year
5
Fiscal Year
1989
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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