Human MHC Class II Constructs For Autoimmume Therapy

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DESCRIPTION (provided by investigator): The goal of this research is to understand and control the activation of pathogenic T cells. Activation of T cells is a multi-step process initiated by co-ligation of antigen-specific T cell receptor (TCR) and co-receptor CD4 with the MHC class II/peptide complex present on antigen presenting cells (APC) (signal I), and includes co-stimulation through T cell surface molecules such as CD28 (signal 2). Our working hypothesis is that T cells can be controlled by regulating the context in which MHC/peptide interacts with the TCR. In order to test this hypothesis we have recently developed a family of novel Recombinant TCR ligands (RTLs) derived from HLADR2 alpha-1 and beta-l domains, with and without a covalently linked peptide antigen. The RTL technology was first described in the context of the animal model of multiple sclerosis, EAE (experimental autoimmune encephalomyelitis). RTLs inhibited activation of pathogenic MBP72-89 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 strong rationale to develop human RTLs and further characterize the mechanism by which the molecules regulate CD4+ pathogenic T cells. We propose to 1) Characterize human RTLs biochemically to enhance the pharmacological utility of the molecules; 2) Study the effect RTLs have on immune synapse formation and quantitate the binding interactions between RTL and TCR using surface plasmon resonance (Biacore); and 3) Characterize the molecular mechanism(s) by which RTLs effect signal transduction and T cell activation, to define the time-frame and context within which RTL treatment can alter effector cells in an antigen-specific manner. Completion of this proposal will identify unique points of intervention for controlling T cells and in turn the T cell immune response and repertoire. Understanding how these unique, rationally engineered drugs work will provide a solid foundation for pharmacological intervention in CD4+ T cell mediated autoimmune diseases.