The investigators have identified one human and seven mouse monoclonal antibodies that induce remyelination in the Theiler's virus model of demyelinating disease. Seven of the antibodies are of the IgM isotype. Each displays broad antigen binding specificity but there does not appear to be a common set of antigens to which all of the antibodies bind. However, each of the antibodies binds to antigens expressed on oligodendrocytes. They recently demonstrated that binding of these antibodies to cultured oligodendrocytes results in gating of extracellular calcium into cells, indicating that there may be a direct effect of binding of these antibodies on the cellular physiology of oligodendrocytes. They propose two main hypotheses regarding the mechanism of action of remyelination promoting antibodies: 1. The antibodies may bind to receptors on the surface of oligodendrocytes or progenitor glial cells to induce remyelination. This hypothesis predicts that a limited repertoire of antibodies with unique specificity to the receptors would function for myelin repair (Direct hypothesis). 2. The antibodies may work by binding to damaged oligodendrocytes or myelin which then triggers a cascade of events by other resident CNS cells (i.e., astrocytes, microglia or neurons) or hematogenous cells (macrophages or immune T cells) which in turn enhances myelin repair. Accumulation of these antibodies at the sites of lesions may act to inhibit macrophage or T cell mediated inflammation and thereby reduce secondary damage to CNS cells. This hypothesis predicts that potentially many polyreactive autoantibodies, with specificity to oligodendrocytes and/or myelin, may be effective in remyelination (Indirect hypothesis). These experiments will examine the roles played by different functional domains of remyelination promoting antibodies and will determine whether different domains exert direct or indirect effects on myelin repair. They will use standard biochemical techniques to generate defined antibody fragments (IgM monomers; F(ab)2 and Fc fragments) and will test these fragments to determine whether they have remyelination promoting activity, whether they have immunomodulatory functions, and whether they have direct effects on oligodendrocytes as indicated by a calcium channel activation assay. These experiments have direct relevance for the development of novel human therapeutics for demyelinating disease.
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