CD4 PEPTIDE ANALOG EFFECT ON EAE

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Multiple sclerosis involves a chronic relapsing inflammatory response that results in demyelination in the central nervous system. CD4+ helper/inducer T cells are involved in the development of the inflammatory responses in the CNS that correlate with multiple sclerosis attacks. Experimental allergic encephalomyelitis (EAE) is an animal model for the study of multiple sclerosis since it shares many of the same clinical and histopathological features as the human disorder, including a primary role for CD4+ T cells in the induction of disease. A major goal of immunological research has been to find an approach that can specifically inhibit those CD4+ T cells that are reacting to central nervous system antigens, without compromising the entire immune system. In this regard, we have recently developed a rationally-designed peptide that was engineered to exhibit the same molecular surface as a portion of the CDR3 region of the murine CD4 molecule. Earlier in vitro experiments have shown that this peptide can inhibit T cell proliferation in mixed lymphocyte reactivity assays and can block activation of both normal T cells and T cell lines after T cell receptor triggering. Theoretically, this peptide acts to uncouple the CD4 molecule from lateral interactions on the T cell surface and thereby interrupts the activation signal to the T cell, with apoptosis as a consequence. Preliminary data in the EAE model indicated that we can inhibit development of clinical disease when this peptide is administered to the mice in either the induction or effector phases. Of most importance, mice examined two weeks after treatment had normal levels of both CD4+ and CD8+ T cells and remained immunoresponsive to alloantigen in a mixed lymphocyte reaction. The current proposal is designed to investigate the efficacy and mechanism of action of the CD4-CDR3 peptide in both acquired and adoptive transfer murine EAE model systems. A clear understanding of the immunological parameters within these murine models would help support the potential application of the CD4-CDR3 peptide analog as a clinical therapeutic agent for multiple sclerosis.