Multiple sclerosis (MS) is a neurological disease of major socioeconomic importance with a suspected virus etiology. Theiler's murine encephalomyelitis virus (TMEV) provides one of the most relevant of the few available experimental animal models of virus-induced demyelination for the following reasons: a) chronic pathological involvement is limited to the white matter of the central nervous system (CNS); b) myelin breakdown leads to clinical disease; c) TMEV persists in the CNS for the life of the mouse; and, d) demyelination appears to be immune-mediated. Our studies during the initial grant period have defined genetic loci contributing to disease susceptibility, established an immune-mediated basis for the development of TMEV-induced demyelinating disease, and defined a critical role for MHC class II-restricted, virus-specific DTH responses in the demyelinating process. We have also demonstrated that chronic CNS demyelination can occur in the apparent absence of neuroantigen-specific autoimmune responses against the major myelin antigens. In addition, our studies have laid the groundwork for future studies on nonspecific (monoclonal antibody therapy) and specific (virus-specific tolerance induction) means of regulating virus and neuroantigen-specific CMI responses. Using in vivo-derived T cells and in vitro-propagated T cell clones/hybrids isolated from both peripheral lymphoid organs and CNS lesions, we propose to continue our research on defining the effector phenotype, epitope-specificity, T cell receptor usage and lymphokine-producing profile of the TMEV-specific T cell repertoire involved in the demyelinating process. We will also continue our studies examining the effects of and mechanisms responsible for both: nonspecific regulation of disease induction via therapy with monoclonal antibodies directed against MHC class I- and class II-restricted T cell subsets, T cell activation antigens, and T cell lymphokines; and, specific regulation of virus-specific immunity (both T cell and antibody levels) and disease induction via TMEV-specific tolerance/suppressor T cell induction. These studies should lead to a definitive understanding of the role of T cell- mediated immune responses in persistent virus-induced demyelinating processes and may be applicable to the understanding of the etiology and treatment of MS.
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