IMMUNOGENETICS OF SUSCEPTIBILITY TO TMEV-INDUCED DEMYELINATION

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This project is directed toward the identification and analysis of the genes affecting the differential susceptibility of different mouse strains to Theiler's murine encephalomyelitis virus (TMEV)- induced demyelinating disease. TMEV-induced demyelinating disease provides an excellent model for human multiple sclerosis (MS), both at a level of clinical symptoms and of histopathology. The disease occurs as the result of an active cell-mediated immune response, probably delayed type hypersensitivity, against the virus which results in "innocent bystander" destruction of myelin. Like human MS, there is a clear genetic influence of disease development, and the identification/analysis of the involved genes may provide clues as to mechanisms (including prevention or alleviation) and genetic risk factors. These will be especially relevant where the equivalent human genes are known which correlate which those defined in these studies. The analysis will proceed along three lines of inquiry. The first is the use of classical methods of genetic analysis, involving the generation and study of Fl and F2 hybirds and backcross progeny between susceptible and resistant strains in order to determine whether susceptibility is a dominant or recessive trait and to make a minimal estimate of the number of genes involved. Subsequent use of appropriate congenic, recombinant, mutant and recombinant-inbred strains will permit the identification and mapping of specific loci. The second phase is to analyse whether resistance to disease occurs (at passively, because the resistant animals lack the immunological "machinery" to carry out the destructive immune response or (b) because they have active mechanisms for preventing the destructive response. These will be analyzed by experiments involving cell transfers between susceptible and resistant animals, and by the use of reagents which affect inhibitory mechanisms such as suppressor T lymphocytes. The third phase will be the analysis of the immune response genetics of resistant and susceptible mouse strains against various viral capsid proteins. We hope to determine if there are particular proteins or epitopes which are differentially recognized by susceptible and resistant strains, and to identify the genes involved in such differential immune responsiveness.