Immune promotion of central nervous system remyelination

Remyelination by oligodendrocytes is the normal response to injury of the central nervous system following experimental demyelination by toxins and viruses in rodents. By contrast, in immune-mediated myelin disorders such as human MS, Theiler's virus-induced demyelination or EAE, remyelination is incomplete. We have considered two hypotheses to explain why myelin repair is incomplete in these disorders. Hypothesis I is that myelin repair is the normal consequence of primary myelin injury but there are immune factors which prevent its full expression. To test hypothesis I, we depleted T cells in Theiler's virus infected mice with cyclophosphamide or with monoclonal antibodies to CD4, CD8, or immune response gene products (Ia). Enhanced remyelination and proliferation of glial cells was observed in mice depleted of CD4+ or CD8+ T cells. Hypothesis II is that there are immune factors within some demyelinated lesions which, when present, promote new myelin synthesis. We envision these factors to be present in those lesions showing remyelination but absent in those lesions that remain demyelinated. To test hypothesis II, we generated polyclonal immunoglobulins directed against normal CNS antigens. Transfer of immunoglobulins from mice immunized repeatedly with spinal cord homogenate resulted in 4-5-fold enhancement of remyelination in Theiler's virus infected mice. We have also generated a series of monoclonal antibodies directed against normal autoantigens which also promote CNS remyelination. These experiments support the concept that full CNS remyelination is possible in human demyelinating diseases such as MS. Manipulation of the immune response either by inhibiting the function of T cells or by treatment with immunoglobulins (possibly normal autoantibodies) appears to promote remyelination. These experiments provide hope for patients with fixed neurological deficits for whom there are currently no available therapies.