IMMUNOGENETICS OF RESISTANCE/SUSCEPTIBILITY TO TMEV INDUCED DEMYELINATION

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Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination leading to clinical signs in susceptible mice. The TMEV system is considered to be one of the best animal models for studying human multiple sclerosis (MS) in light of the potential viral etiology and similarities in the progression of chronic demyelination. Extensive studies on the class II-restricted, CD4+ T cell response specific for TMEV, which appears to play an important role in the viral pathogenesis, have been reported. However, very little is known about the class I-restricted, CD8+ T cell response against TMEV, despite that this type of response is known to be the most efficient in protecting the host from viral infections. The resistance/susceptibility of mice to TMEV-induced demyelinating disease is controlled by the MHC, particularly by the H-2D locus coding for a class I molecule. Using beta2- microglobulin (beta2M) deficient mice lacking class molecules, we have further demonstrated that the effect of the MHC may represent a protective (or regulatory) role for this virus-induced demyelinating disease. In addition, such a CD8+ T cell population appears to be involved in the resistance of some BALB/c substrains. Based on our preliminary results, we hypothesize that MHC class II-restricted Th1 population is responsible for the development of disease and class I (H-2D)-restricted CD8+ cells are responsible for protection from the disease. We propose here to examine the potential role of MHC class I-restricted cytotoxic T cells in the protection and/or pathogenesis of Theiler's virus-induced demyelinating disease as a model for human multiple sclerosis. The specific aims for the proposed studies include: 1) To generate stable target cells expressing viral antigens in conjunction with proper MHC class antigens by viral DNA transfection; 2) To assess the level of MHC class I-restricted T cells specific for viral antigens in resistant and susceptible mice during the course of demyelination; 3) To establish TMEV-specific, class I-restricted T cell clones and analyze their roles in TMEV-IDD; and 4) To identify the viral epitopes involved in the cytotoxic T cell reactivity. We believe that our proposed studies will yield important information on the potential control mechanism(s) against virus-induced, immune-mediated demyelination, which is a relevant animal model for studying human MS.