Targeting of IgMkappa antibodies to oligodendrocytes promotes CNS remyelination.
We previously identified the remyelinating activity of a natural IgMkappa oligodendrocyte-reactive autoantibody (SCH94.03), using a virus-induced murine model of multiple sclerosis. We now describe a second mouse IgMkappa monoclonal antibody (mAb) (SCH79.08) raised against normal mouse spinal cord homogenate, which reacts with myelin basic protein and also promotes remyelination. Because these two mAbs recognize different oligodendrocyte antigens, several previously identified oligodendrocyte-reactive IgMkappa mAbs (O1, O4, A2B5, and HNK-1), each with distinct antigen specificities, were evaluated and found to promote remyelination. In contrast, IgMkappa mAbs that did not bind to oligodendrocytes showed no remyelination. One of these, CH12 IgMkappa mAb, which shares variable region cDNA sequences with SCH94.03 except for amino acid differences in the complementarity-determining region 3 in both heavy and light chains, did not bind to oligodendrocytes and did not promote remyelination. The fact that multiple oligodendrocyte-reactive antibodies with distinct antigen reactivities induce remyelination argues against direct activation by a unique cell surface receptor. These findings are most consistent with the hypothesis that the binding of mAbs to oligodendrocytes in the lesions induces myelin repair via indirect immune effector mechanisms initiated by the mu-chain. Importantly, these studies indicate that oligodendrocyte-reactive natural autoantibodies may provide a powerful and novel therapeutic means to induce remyelination in multiple sclerosis patients.
Asakura
K
K
Department of Neurology, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Miller
D J
DJ
Pease
L R
LR
Rodriguez
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology*; D000956:Antigens, Viral / Q000032:analysis / Q000276:immunology; D001323:Autoantibodies / Q000235:genetics / Q000494:pharmacology; D015153:Blotting, Western; D001921:Brain / Q000276:immunology*; D018076:DNA, Complementary; D003711:Demyelinating Diseases / Q000276:immunology / Q000628:therapy; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes; D005838:Genotype; D007075:Immunoglobulin M / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D009186:Myelin Sheath / Q000276:immunology*; D009416:Nerve Regeneration / Q000276:immunology*; D009836:Oligodendroglia / Q000502:physiology*; D010641:Phenotype; D011051:Poliomyelitis / Q000276:immunology / Q000628:therapy; D017945:Theilovirus
D000911:Antibodies, Monoclonal; D000956:Antigens, Viral; D001323:Autoantibodies; D018076:DNA, Complementary; D000939:Epitopes; D007075:Immunoglobulin M; D007135:Immunoglobulin Variable Region; C101676:SCH94.03 monoclonal antibody