The interaction between the MHC/peptide-antigen complex and the T cell receptor (TCR) is essential for antigen-specific T cell activation. Antigen analogs can act as powerful and specific inhibitors of T cell activation and provide a rational approach to antigen-specific immuno-intervention in allergies and autoimmune diseases. Lewis rats immunized with myelin basic protein (MBP) or MBP peptides develop experimental autoimmune encephalomyelitis (EAE), a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CNS) that is used as a model for the human disease multiple sclerosis (MS). In the Lewis rat model of EAE, T cells specific for MBP-72-89 dominate the autoimmune response and TCR expression on the pathogenic T cells is well characterized. This model provides an excellent opportunity to test the hypothesis that regulating the context in which MHC/peptide interacts with TCR can be used to control antigen-directed T cell activation. We have recently developed a family of novel molecules derived from the rat MHC class II alpha-1 and beta-1 domains, with and without a genetically linked polypeptide epitope. Both the non-covalent and covalent beta1alpha1/MBP-72-89 constructs inhibited activation of pathogenic MBP-72-89 reactive T cells and could be used to prevent and treat EAE. The potential of these molecules in the treatment of human autoimmune disease provides a strong rationale to further characterize the mechanism by which these molecules regulate CD4+ pathogenic T cells. We propose to 1) Characterize the beta1alpha1 molecules biochemically; 2) Determine the specificity of the beta1alpha1/peptide molecules by direct binding studies to define the interaction surface between the TCR and beta1alpha1/peptide molecules; 3) To characterize the in vitro effects of the beta1alpha1/peptide molecules and define the time-frame and context within which beta1alpha1/peptide treatment can alter the activation of effector cells in response to antigen stimulation; and 4) To characterize the in vivo effects of the beta1alpha1/peptide molecules, with the goal of defining the mechanism by which the beta1alpha1/peptide molecules block the induction of EAE in vivo.
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