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

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

Departments of ^*Neurology, ^†Immunology, and ^‖Hematology, Mayo Medical and Graduate Schools, Rochester, MN 55905; ^¶Institut National de la Santé et de la Recherche Médicale (INSERM) U430, Paris, France; and ^§Department of Neurology, Nagoya University School of Medicine, Nagoya, 466-8550 Japan

Edited by John B. Robbins, National Institutes of Health, Bethesda, MD, and approved April 11, 2000 (received for review December 27, 1999)

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 virus-mediated 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.

Footnotes

↵ ‡ A.E.W. and K.A. contributed equally to this work.
↵ ** To whom reprint requests should be addressed at: Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail: rodriguez.moses{at}mayo.edu.
This paper was submitted directly (Track II) to the PNAS office.
Data deposition: The sequences reported in this paper have been deposited in the GenBank database (accession nos. AF212992 and AF212993).
Abbreviations:

CNS,

central nervous system;

IVIg,

human i.v. IG;

MS,

multiple sclerosis;

OL,

oligodendrocyte, SC, Schwann cell;

sHIgM,

serum-derived human monoclonal IgM;

TMEV,

Theiler's murine encephalomyelitis virus