The ultimate goal of this research is to achieve the induction of clinical tolerance (antigen specific unresponsiveness) allowing the long- term survival of human organ allografts. Collaborative studies between the Krensky, Clayberger, and Parham laboratories have shown that synthetic peptides corresponding to linear sequences of HLA class I molecules are potent inhibitors of the allogeneic immune response, both in vitro and in vivo. The objectives of the studies proposed here are to broaden our understanding of this phenomenon by elucidating the mechanisms responsible for these effects (Project 1), to define the ligand(s) and binding characteristics involved (Project 2), to extend pre-clinical studies in rat transplantation models (Project 3), and, eventually to develop a protocol applicable to human allogeneic organ transplantation. These projects are supported by an Administrative Core (A) designed to ensure unity of purpose and quality control and a Peptide Chemistry Core (B) responsible for peptide synthesis and modification. This program builds upon established collaborations between transplant clinicians, clinical scientists, and basic immunologists in order to rapidly apply knowledge obtained from basic research to clinical practice. This proposal is designed to provide a rational basis for the application of HLA derived peptides to transplantation. It is aimed at providing the foundation for renewal application which would propose specific human trials and uniquely monitor the human in vivo immune response to such therapies.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI035125-02
Application #
2070549
Study Section
Special Emphasis Panel (SRC (23))
Project Start
1993-09-30
Project End
1997-06-30
Budget Start
1994-07-01
Budget End
1995-06-30
Support Year
2
Fiscal Year
1994
Total Cost
Indirect Cost
Name
Stanford University
Department
Pediatrics
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
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Boytim, M L; Lyu, S C; Jung, R et al. (1998) Inhibition of cell cycle progression by a synthetic peptide corresponding to residues 65-79 of an HLA class II sequence: functional similarities but mechanistic differences with the immunosuppressive drug rapamycin. J Immunol 160:2215-22
Pattison, J M; Krensky, A M (1997) New insights into mechanisms of allograft rejection. Am J Med Sci 313:257-63
Krensky, A M; Clayberger, C (1996) Structure of HLA molecules and immunosuppressive effects of HLA derived peptides. Int Rev Immunol 13:173-85
Nossner, E; Goldberg, J E; Naftzger, C et al. (1996) HLA-derived peptides which inhibit T cell function bind to members of the heat-shock protein 70 family. J Exp Med 183:339-48
Krensky, A M; Clayberger, C (1995) Human leukocyte antigen-derived peptides as novel immunosuppressives. Proc Assoc Am Physicians 107:81-5
Krensky, A M; Clayberger, C (1994) Transplantation immunology. Pediatr Clin North Am 41:819-39
Nisco, S; Vriens, P; Hoyt, G et al. (1994) Induction of allograft tolerance in rats by an HLA class-I-derived peptide and cyclosporine A. J Immunol 152:3786-92