An important question in multiple sclerosis (MS) research is why there is absence of full remyelination and functional recovery following demyelinating disease. Morphologic studies suggest that CNS remyelination does occur in the MS lesion but the process is incomplete. We have considered two hypotheses to explain the absence of full remyelination in MS. Hypothesis I is that there are factors within some demyelinated lesions which when present promote new myelin synthesis. Hypothesis II is that CNS remyelination is the normal consequence of primary myelin injury but there are immune factors which prevent its full expression. Most recently we have shown that immunoglobulins (Igs) may be one of the important factors that promote remyelination. We have also generated a monoclonal antibody (mAb) designated 94.03 which recognizes an antigen on the surface of oligodendrocytes and promotes CNS remyelination in vivo. Our first goal will be to identify the cDNA (designated remyelination """"""""REM"""""""" cDNA) encoding the surface protein on oligodendrocytes recognized by mAb 94.03. We will screen for cell surface expression on COS cells of the 94.03 defined epitope using a rat brain cDNA expression library. The functional significance of the identified clones will be verified by correlating epitope expression with mRNA expression. In addition, we will generate abs to peptides of the derived protein encoded by REM cDNA to determine that this antigen is important in immune-mediated remyelination. We have shown previously that depletion of CD4 or CD8 T cells using mAb therapy promotes CNS remyelination in animals chronically infected with Theiler's virus. In the second specific aim we will determine the components of the immune response in vivo which inhibit CNS remyelination by characterizing CNS remyelination and virus persistence in TMEV-infected mice that have been rendered immune deficient by knockout technology. In the third specific aim we will determine whether in vivo treatment with mAb 94.03 synergizes to enhance CNS remyelination in immune """"""""knockout"""""""" mice. This has important relevance to clinical medicine because it would indicate that Ig treatment along with immunosuppression may enhance CNS remyelination. In the fourth specific aim we will address whether remyelination observed in these models results in functional improvement. Using a new technique in the mouse to measure motor-evoked and sensory-evoked conduction velocities, we will determine whether the therapeutic approaches to promote remyelination improves conduction. These experiments have the potential to elucidate new strategies for the promotion of remyelination in the CNS.
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