IMMUNOPATHOGENESIS OF VIRUS-INDUCED DEMYELINATION

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C57B1/6 (B6) mice infected with the neurotropic coronavirus, mouse hepatitis virus, strain JHM, develop a demyelinating encephalomyelitis with clinical signs of hindlimb paralysis. The clinical and pathological features of this disease have many similarities to the human disease, multiple sclerosis. One important similarity between MS and the MHV-infected mouse is that the host immune response is critical for the development of demyelination. The applicant has recently shown that MHV infection of mice that lack mature T and B cells due to a deficiency in recombinase-activating gene activity (Rag1 -/- mice) do not develop demyelination unless splenocytes from immunocompetent B6 are adoptively transferred. Demyelination then occurs reproducibly in 6-7 days. In addition, he has adapted methods for identifying antigen-specific CD4 and CD8 T cells (soluble MHC/peptide tetramer assays and assays for measuring intracellular interferon-gamma production) to the direct ex vivo analysis of lymphocyte harvested from mice with MHV-induced neurological disease. The central hypothesis of this proposal is that adoptively transferred CD4 or CD8 T cells secrete a factor or perform a function (or both) that is critical for the induction and/or propagation of the demyelinating process in Rag -/- mice. This hypothesis will be approached in the following three specific aims. 1. To determine if antigen-specific CD4 or CD8 T cells in the absence of the other subset are sufficient to induce and propagate the demyelinating process. The contribution of Fas/FasL interactions and of specific chemokines and cytokines will also be determined. 2. To investigate the role of nitric oxide and axonal degeneration, two potentially key components of the pathogenic process, in the adoptive transfer model of demyelination. 3. To determine whether MHV antigen-nonspecific CD4 T cells become activated and contribute to demyelination in virus-infected mice. These experiments will take advantage of recent advances in our ability to detect antigen-specific CD4 T cells in the MHV-infected CNS. Demyelination is rapid and reproducible after adoptive transfer into the MHV-infected Rag1 -/- mice, making this a unique system for investigating the pathogenesis of virus-induced demyelination and answering questions about virus-induced demyelination.