Over the previous funding period, a detailed analysis of the interaction between peptide and MHC molecules was made. During the course of those investigations, a novel mechanism by which analogs of peptide antigens inhibit the recognition of those antigens by T cells was made. It was found that certain antigen analogs not only competed with antigen for binding to MHC, but the antigen analog/MHC complexes could also compete with antigen/MHC complexes for binding to the T cell receptor. This application extends the observations on """"""""T-cell receptor antagonism"""""""" to explore the following issues: First, a series of experiments to examine the potential use of antigen analogs to intervene in the course of an autoimmune disease will be performed. To do this, the capacity of one or a few analogs to inhibit polyclonal antigen-specific responses needs to be established. Next, the capacity of such analogs to inhibit an in vivo disease process will be evaluated, using experimental allergic encephalitis as the model. Since the potential medical use of analogs is dependent upon knowledge of the nature of specific autoantigens involved in the pathogenesis of autoimmune disease, an effort will be made to identify the autoantigens involved in the NOD mouse model of diabetes. The relationship between T cell receptor antagonism elicited by antigen analogs and the capacity of analogs to induce incomplete stimulation of T cells (partial anergy), as described by Paul Allen, will also be assessed. Specifically, questions concerning the structural relationship of analogs that are TCR antagonists and those that are partial agonists will be defined, as will the capacity of these different analogs to elicit early signaling events such as tyrosine phosphorylation. Finally, the analysis of the biologic effects of antigen analogs will also be evaluated in a TCR transgenic system. The structural relationship of analogs that stimulate peripheral T cells and those that induce positive and negative selection in the thymus will be analyzed. This will allow an evaluation of an affinity hypothesis to explain thymic -differentiation events.
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