The goal of this research is to understand and control the activation of pathogenic T cells. 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. Recent studies have lead to the development of a platform molecular RecombinantTCR Ligand (RTL) technology derived from domains of MHC Class II molecules. These protein therapeutics have demonstrated direct antigen-specific binding and inhibition of pathogenic T cells. Furthermore, these molecules could be used to prevent and treat experimental autoimmune encephalomyelitis (EAE), a CD4+, Th1 cell-mediated demyelinating disease of the central nervous system (CMS)that is used as a model for the human disease multiple sclerosis (MS).During the tenure of this proposal RTLs will be characterized using relapsing- remitting and chronic models of EAE,allowing us to explore the molecular and systemic mechanism(s) by which RTLs control pathogenic T cells in vivo. We propose the following specific aims:
SPECIFIC AIM 1. Biochemical and biophysical characterization of l-As-and l-AB-derived Recombinant TCR Ligands (RTLs).
SPECIFIC AIM 2. Characterization of the molecular mechanism(s) by which RTLs effect T cell activation in vitro.
SPECIFIC AIM 3. Evaluation of the in vivo effects RTLs have on relapsing-remitting and chronic models of EAE. The work proposed will provide a solid base for pharmacological intervention in CD4+ T cell mediated autoimmune diseases.
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