Intracerebral inoculation of Theiler's murine encephalomyelitis virus (TMEV) results in chronic inflammatory demyelination which readily correlates with clinical signs in susceptible mice. The TMEV system is considered to be a relevant animal model for studying human multiple sclerosis (MS) in light of the similarities in the chronic nature of demyelination and the potential viral etiology of human MS. Despite the relevance of this system to human MS, very little is known about the viral epitopes which might be involved in pathogenesis due mainly to the complexity of the viral antigens. We have recently identified predominant linear antibody epitopes of the viral capsid proteins using various synthetic peptides and fusion proteins derived from recombinant gammagt11 clones. Interestingly, only one of the epitopes is preferentially recognized by antibodies in cerebrospinal fluid from clinically affected SJL mice following viral infection. In addition, we have develop an in vivo experimental system to assess the pathogenic role of viral epitopes. Furthermore, we have established several T cell lines/clones specific for TMEV variants which do not result in demyelinating disease but induce a protective immunity to subsequent infection with pathogenic virus. By applying these utilities of our preliminary results, we propose to correlate the differences in epitope recognition by antibodies and T cells with their involvement in the TMEV- induced demyelination.
Three specific aims are proposed in this application: (1) Identification of viral epitopes involved in virus- induced demyelination, using fusion proteins, synthetic peptides as well as non-pathogenic variant viruses; (2) Assessment of the role of linear antibody epitopes in the virally induced demyelinating process; and (3) Analysis of infiltrating T cells in the CNS from virus-infected mice, including TCR usage, lymphokine production and epitope recognition. We believe that our proposed studies will yield important information on virally induced, immune-mediated demyelination, which appears to be a relevant, realistic animal model system for studying human MS.
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