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

Abstract

Promoting remyelination, a major goal of an effective treatment for demyelinating diseases, has the potential to protect vulnerable axons, increase conduction velocity, and improve neurologic deficits. Strategies to promote remyelination have focused on transplanting oligodendrocytes (OLs) or recruiting 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 remyelination in a virusmediated model of multiple sclerosis. Four additional OL-binding human mAbs did not promote remyelination. Both human mAbs were as effective as human i.v. Ig, a treatment shown to have efficacy in multiple sclerosis, and bound to the surface of human OLs suggesting a direct effect of the mAbs on the cells responsible for myelination. Alternatively, targeting human mAbs to areas of central nervous system (CNS) pathology may facilitate the opsonization of myelin debris, allowing repair to proceed. Human mAbs were isolated from the sera of individuals with a form of monoclonal gammopathy. 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 with the hypothesis that CNS-reactive mAbs, part of the normal Ig repertoire in humans, may help repair and protect the CNS from pathogenic immune injury, and (ii) further challenge the premise that Abs that bind OLs are necessarily pathogenic. E nhancement of remyelination and protection from axonal injury are important therapeutic goals in the treatment of inflammatory demyelinating central nervous system (CNS) disorders such as multiple sclerosis (MS). Remyelination in MS plaques can occur, but is limited (1, 2) even though oligodendrocyte (OL) progenitors are present in the adult (3, 4). A number of therapeutic strategies to promote remyelination have been tested in experimental animals. Transplantation of OLs (5) or their progenitors (6) into demyelinated tissue produces new myelin. Transplanted OL progenitors also can remyelinate demyelinated lesions in the adult CNS (7) and migrate toward an area of damage when placed in close proximity to the lesion (8). Unresolved issues remain concerning the survival of transplanted OL progenitors in the intact adult CNS and their ability to target to areas of myelin pathology (9). However, if CNS lesions are surgically approachable and axons are still intact, transplantation of glial cells may be a viable therapy for improving functional performance (10).The in vitro administration of growth or trophic factors induces the expansion of OL progenitors (11, 12) or promotes mature OLs to dedifferentiate and subsequently reinitiate a program of myelination (13,14). The in vivo administration of trophic factors via genetically engineered fibroblasts to the injured CNS promotes ax...

Therapeutic Action of Cannabinoids in a Murine Model of Multiple Sclerosis

“…JWH-015 was injected at 0.6 mg/kg for 3 d, 0.9 mg/kg on days 4 -6, and 1.2 mg/kg on the last 4 d. Vehicle-injected mice received a solution of 5% BSA and 0.2% DMSO in PBS. The number of mice for each treatment was 12; half were killed to process the spinal cord the day after treatment termination, and the remainder were maintained for 25 d to reach 5 weeks from the beginning of treatment; this period is considered optimal to evaluate remyelination induced by any event (Warrington et al, 2000).…”

Polyreactive myelin oligodendrocyte glycoprotein antibodies: Implications for systemic autoimmunity in progressive experimental autoimmune encephalomyelitis

“…Recently, several autoantibodies of the IgM isotype, including a few oligodendrocytereactive antibodies, have been demonstrated to promote remyelination in the Theiler's murine encephalomyelitis virus-induced model for MS (Asakura et al, 1998;Miller et al, 1994;Miller and Rodriguez, 1995). These antibodies promoting remyelination also have the characteristics of "natural autoantibodies" (Asakura et al, 1995;Asakura et al, 1998;Warrington et al, 2000). Natural autoantibodies are mostly of the IgM isotype, have polyreactivity toward multiple self and nonself antigens and are encoded by germline Ig genes with little or no mutations (Asakura et al, 1995;Kirschning et al, 1999;Miller and Rodriguez, 1995).…”

Review: New advances in the treatment of neurological diseases using high dose intravenous immunoglobulins

“…repair by IVIg originates from a number of experimental studies in the animal model of Theiler's virus mouse encephalitis (TMEV) [Warrington et al 2000;Bieber et al 2001]. In patients with long-standing clinical deficits in MS, three studies could not demonstrate a clinical or neurophysiological improvement induced by IVIg [Stangel et al 2000;Noseworthy et al 2000;Noseworthy et al 2001].…”