Theiler's virus encephalomyelitis of mice is characterized by prolonged white matter disease whose main features are inflammation of mononuclear cell type and demyelination mainly in the anterior and lateral columns of the spinal cord. This demyelination is always associated with the inflammatory activity and is accomplished by two main mechanisms: one is characterized by vesicular disruption of myelin; the second by stripping of myelin lamellae by invading processes of mononuclear cells. Both mechanisms of demyelination evolving in close association with infiltrating mononuclear cells are identical to the demyelinating processes which have been repeatedly described in experimental allergic encephalomyelitis, the prototype of autoimmune demyelinating diseases. As strong support to the possibility of Theiler's demyelination also being on an immunopathologic basis, we immunosuppressed animals with either cyclophosphamide or rabbit antithymocyte serum and in both instances both inflammation and demyelination were prevented. Prevention of the disease through immunosuppression strongly suggests that demyelination is indeed immune mediated, a conclusion that makes this animal model relevant to Multiple Sclerosis in humans where virus induced, immune mediated demyelination is strongly suggested. We are now in the process of investigating the mechanisms of immune mediated demyelination. We are trying to determine the optimal dosage and schedule of immunosuppression for adoptive immunization experiments. Also, immunohistochemical studies have been started aimed at demonstrating the presence of anti-viral or anti-myelin antibody in the numerous plasma cells which are present in the inflammatory infiltrates. Studies for visualizing viral antigen and its relation to the demyelinating activity have also been started. So far the best method of peroxidase conjugation is being sought and the test virus we chose is a very large rhabdovirus, vesicular stomatitis virus. Some encouraging results of specific viral localization have been obtained and experiments with Theiler's virus are soon to begin. Theiler's virus cannot be seen by routine E.M. in our infected animals and it could be that it persists as non-structural antigen perhaps attached to myelin and therefore conducive to myelin destruction by eliciting an antiviral reaction. Ultrastructural immuno-histochemistry should help in elucidating this problem.