The primary goal of this research is to develop a therapeutic approach to multiple sclerosis (MS) and other demyelinating conditions that uses naturally occurring autoantibodies directed against human oligodendrocytes to enhance remyelination. Promoting remyelination has the potential to protect vulnerable axons, increase axon conduction velocity, and improve neurologic deficits. Several polyreactive mouse IgM monoclonaI antibodies (mAbs) have been identified that recognize oligodendrocyte surface antigens and promote remyelination in mouse models of MS. More recently, utilizing an antigen4ridependent screening strategy, human mAbs have been identified, that bind to both rodent and human oligodendrocytes, and promote central nervous system (CNS) remyelination in mice. These results suggest that CNS antigen-specific antibodies that can enhance CNS repair are part of the normal immunoglobulin repertoire. Increasing the serum concentration of these CNS-reactive mAbs may help protect the CNS from pathogenic immune injury and promote myelin repair. Treatment with human remyelination- promoting mAbs may therefore be an effective and easily implemented therapy for human demyelinating conditions. The goal of this project is to develop a vector system for the high level expression of human IgM antibodies in transfected cells in culture and to use this system to produce human remyelination promoting antibodies for studies with the mouse models of demyelinating disease. The development of this system would represent a small scale model for the production of antibody for clinical trials in humans. Anti-idiotype antibodies will also be generated for use in the quantification and characterization of the remyelination promoting antibodies during production and as tools to monitor the antibodies during therapy.
The monoclonal antibodies (Mabs) to be developed in this grant have potential important applications as promoters of remyelination in the central nervous system Demyelinating conditions such as multiple sclerosis affect over half a million Americans and represent over $14 billion in annual costs to society in the U.S. alone. Currently available therapies for MS may slow progression of disease but do not repair existing demyelination of the CNS.