Direct evidence that a human antibody derived from patient serum can promote myelin repair in a mouse model of chronic-progressive demyelinating disease.
Certain human sera from patients with monoclonal gammopathies contain factors that induce myelin repair in animals with demyelinating disease. We hypothesize that antibodies functionally distinguish the serum of one patient from another. However, pooled normal polyclonal human IgM antibodies also induce remyelination. Definitive proof that specific antibodies are the biologically active components of serum is missing because unquestionably pure preparations of antibody molecules cannot be generated by fractionation. To demonstrate definitively that antibody is the biologically active component of patient serum, recombinant antibody was generated for evaluation in bioassays. The induction of remyelination in vivo requires milligram quantities of antibody. Consequently, an expression system was engineered to express high-titer, recombinant human IgM antibodies in vitro. A resulting recombinant antibody (rHIgM22) was evaluated for its ability to induce remyelination in the Theiler's virus mouse model of chronic-progressive demyelinating disease. We demonstrate that a single recombinant monoclonal antibody recapitulates the key characteristics of patient serum, including binding specificity, the induction of calcium signals in oligodendrocytes in vitro, and the induction of myelin repair within demyelinated plaques in vivo. The rHIgM22 antibody provides a new venue for the analysis of mechanisms governing remyelination and may prove useful in the treatment of demyelinating diseases.
Mitsunaga
Yoshihiro
Y
Department of Neurology, Mayo Medical and Graduate Schools, Mayo Clinic, Rochester, Minnesota 55905, USA.
Ciric
Bogoljub
B
Van Keulen
Virginia
V
Warrington
Arthur E
AE
Paz Soldan
Mateo
M
Bieber
Allan J
AJ
Rodriguez
Moses
M
Pease
Larry R
LR
D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use*; D001253:Astrocytes / Q000378:metabolism; D001921:Brain / Q000166:cytology; D020013:Calcium Signaling; D002478:Cells, Cultured; D002908:Chronic Disease; D020278:Demyelinating Autoimmune Diseases, CNS / Q000473:pathology / Q000628:therapy*; D018450:Disease Progression; D018014:Gene Transfer Techniques; D006801:Humans; D007106:Immune Sera / Q000276:immunology / Q000494:pharmacology; D007075:Immunoglobulin M / Q000235:genetics / Q000494:pharmacology / Q000627:therapeutic use; D051379:Mice; D008954:Models, Biological; D009186:Myelin Sheath / Q000473:pathology; D009836:Oligodendroglia / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology
D000911:Antibodies, Monoclonal; D007106:Immune Sera; D007075:Immunoglobulin M; D011994:Recombinant Proteins