The interaction of lympocytes with HLA molecules is a crucial event in immunobiology. We have recently shown that peptides corresponding to short linear sequences of HLA molicules can specifically inhibit cytolytic T lymphocyte (CTL) mediated cytolysis. This finding has important biologic and clinical significance. Biolobically, this finding suggests that the allogeneic response is a special case of nominal antigen recognition. That is, it appears that in some cases allogeneic HLA is seen as degraded peptides (or fragments) in the context of whole HLA. Clinically, this information is fundamental to the design of both inhibitory and/or stimulatory immunotherapy. Not only can peptides be used to modulate CTL effector function, but they may also be used diagnostically to define T cell clones of a particular specificity. Peptides may be altered in a variety of ways depending upon their ultimate purpose. The studies proposed here are designed to define the mechanism and biologic significance of peptide binding and inhibition. Specifically, we propose to: 1) define the molecular basis of inhibition of cytolysis by peptides, 2) use these peptides to investigate the mechanism of allogeneic recognition, 3) develop a panel of anti-clonotypic antibodies recognizing the T cell receptor from a series of HLA-A2 specific CTL, and 4) investigate the receptors. These studies will prove relevant to the immunobiology diagnosis, and therapy of cancer, transplant rejection, and autoimmune diseases.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA047609-05
Application #
3191345
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1988-04-01
Project End
1993-03-31
Budget Start
1992-04-01
Budget End
1993-03-31
Support Year
5
Fiscal Year
1992
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305
Krensky, A M (1994) T cells in autoimmunity and allograft rejection. Kidney Int Suppl 44:S50-6
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
Krensky, A M; Lyu, S C; Pouletty, P et al. (1993) Peptides corresponding to the CD8 binding region of HLA class I block the differentiation of cytotoxic T lymphocyte precursors. Transplant Proc 25:483-4
Wesley, P K; Clayberger, C; Lyu, S C et al. (1993) The CD8 coreceptor interaction with the alpha 3 domain of HLA class I is critical to the differentiation of human cytotoxic T-lymphocytes specific for HLA-A2 and HLA-Cw4. Hum Immunol 36:149-55
Buxton, S E; Benjamin, R J; Clayberger, C et al. (1992) Anchoring pockets in human histocompatibility complex leukocyte antigen (HLA) class I molecules: analysis of the conserved B (""45"") pocket of HLA-B27. J Exp Med 175:809-20
Krensky, A M (1991) Molecular basis of transplant rejection and acceptance. Pediatr Nephrol 5:422-7
Clayberger, C; Rosen, M; Parham, P et al. (1990) Recognition of an HLA public determinant (Bw4) by human allogeneic cytotoxic T lymphocytes. J Immunol 144:4172-6
Krensky, A M; Weiss, A; Crabtree, G et al. (1990) T-lymphocyte-antigen interactions in transplant rejection. N Engl J Med 322:510-7
Krensky, A M; Clayberger, C (1989) The molecular basis of renal transplant rejection. Semin Nephrol 9:116-9
Hogan, K T; Clayberger, C; Bernhard, E J et al. (1989) A panel of unique HLA-A2 mutant molecules define epitopes recognized by HLA-A2-specific antibodies and cytotoxic T lymphocytes. J Immunol 142:2097-104

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