Strategies to Promote Central Nervous System Remyelination In Vivo

Abstract

One important goal of multiple sclerosis research is to develop strategies to promote remyelination in the central nervous system (CNS). We previously reported that immunoglobulins directed against spinal cord homogenate promote CNS remyelination when injected into Theiler’s virusinfected mice. To elucidate the mechanism of immunoglobulin-mediated CNS remyelination, we generated a monoclonal antibody (designated SCH94.03) against spinal cord homogenate, which increases remyelination four-fold when injected into SJL/J mice with Theiler’s virus-induced demyelination. In live cell staining, SCH94.03 recognizes a surface antigen on well-differentiated oligodendrocytes. Double labeling experiments with other oligodendrocytespecific antibodies indicate that this surface antigen may be a novel antigen on oligodendrocytes. In contrast with the surface labeling, SCH94.03 recognizes intracellular antigen(s) resembling cytoskeleton protein in all cells. Immunoglobulin cDNA sequence analysis reveals that SCH94.03 is encoded by immunoglobulin germline genes without somatic mutations, consistent with the conclusion that SCH94.03 is a natural autoantibody. SCH94.03 is also polyreactive toward multiple protein antigens and chemical haptens by ELISA. We propose and discuss three possible mechanisms of immunoglobulin-mediated CNS remyelination based on the results obtained from the Theiler’s virus model of multiple sclerosis.