Human monoclonal antibodies reactive to oligodendrocytes promote remyelination in a model of multiple sclerosis

Promoting remyelination, a major goal of an effective treatment for demyeli nating diseases, has the potential to protect vulnerable axons, increase co nduction velocity, and improve neurologic deficits, Strategies to promote r emyelination have focused on transplanting oligodendrocytes (OLs) or recrui ting endogenous myelinating cells with trophic factors. Ig-based therapies, routinely used to treat a variety of neurological and autoimmune diseases, underlie our approach to enhance remyelination, We isolated two human mAbs directed against OL surface antigens that promoted significant remyelinati on in a virus-mediated model of multiple sclerosis, Four additional OL-bind ing human mAbs did not promote remyelination, Both human mAbs were as effec tive as human i.v. Ig, a treatment shown to have efficacy in multiple scler osis, and bound to the surface of human OLs suggesting a direct effect of t he mAbs on the cells responsible for myelination. Alternatively, targeting human mAbs to areas of central nervous system (CNS) pathology may facilitat e the opsonization of myelin debris, allowing repair to proceed. Human mAbs were isolated from the sera of individuals with a form of monoclonal gammo pathy, These individuals carry a high level of monoclonal protein in their blood without detriment, lending support to the belief that administration of these mAbs as a therapy would be safe. Our results are (i) consistent wi th the hypothesis that CNS-reactive mAbs, part of the normal Ig repertoire in humans, may help repair and protect the CNS from pathogenic immune injur y, and (ii) further challenge the premise that Abs that bind OLs are necess arily pathogenic.