Monoclonal autoantibodies promote central nervous system repair in an animal model of multiple sclerosis.
Susceptible strains of mice infected intracerebrally with Theiler's murine encephalomyelitis virus develop a chronic, progressive, immune-mediated CNS demyelinating disease similar both pathologically and clinically to multiple sclerosis. Previous reports indicated that polyclonal immunoglobulins from mice injected with homogenized spinal cord promote CNS remyelination when given to SJL/J mice chronically infected with Theiler's virus. To explore further both the mechanism(s) and potential therapeutic usefulness of antibodies in the treatment of CNS demyelinating diseases, we made a panel of monoclonal antibodies derived from splenocytes of SJL/J mice injected with homogenized spinal cord, and screened them for their autoantigen-binding capability. Monoclonal IgM autoantibodies from two clones, designated SCH94.03 and SCH94.32, promoted fourfold more CNS remyelination than controls when given to chronically infected SJL/J mice. CNS remyelination, assessed morphologically by the presence of abnormally thin myelin sheaths relative to axonal diameter, correlated with the absence of clinical disease progression. In titration experiments, treatment with SCH94.03 and remyelination had a positive dose-response relationship, and as little as 10 micrograms of antibody promoted remyelination. Both SCH94.03 and SCH94.32 showed multiorgan autoreactivity, and recognized both surface and cytoplasmic determinants on glial cells. We propose that this model provides a unique system to elucidate the mechanism(s) and test the reparative potential of autoantibodies in the treatment of CNS injury.
Miller
D J
DJ
Department of Immunology, Mayo Clinic and Foundation, Rochester, Minnesota 55905.
Sanborn
K S
KS
Katzmann
J A
JA
Rodriguez
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000502:physiology*; D000918:Antibody Specificity; D001323:Autoantibodies / Q000502:physiology*; D002490:Central Nervous System / Q000276:immunology* / Q000473:pathology / Q000648:ultrastructure; D004195:Disease Models, Animal; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008854:Microscopy, Electron; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology; D009186:Myelin Sheath / Q000276:immunology* / Q000473:pathology / Q000648:ultrastructure; D009416:Nerve Regeneration / Q000276:immunology*; D017945:Theilovirus
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; C101676:SCH94.03 monoclonal antibody