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.
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