Little is known about the molecular biology of remyelination and even less about the role of antibodies in promoting this process. We propose two general hypotheses by which antibodies might promote remyelination. The antibodies may act by binding to unique receptors on the surface of oligo-dendrocytes or progenitor glial cells to induce remyelination, the direct hypothesis. Alternatively, the antibodies may work by binding to damaged oligodendrocytes or myelin, which then triggers a cascade of events by other resident CNS cells (astrocytes, microglia or neurons) or hematogenous cells (macrophages or immune T-cells), which in turn enhances myelin repair, the indirect hypothesis.
Since many of the mouse and human remyelina-tion-promoting antibodies bind to oligodendrocytes and/or myelin, it is reasonable to hypothesize a direct effect on the cells being recognized. Work by
Figure 5.2 Human monoclonal antibody sHIgM22 binds to oligodendrocytes in culture. Cultured human oligodendrocytes were maintained in serum-free media for 3 weeks prior to immunolabeling. Human oligodendrocytes were identified by their labeling with 04 mAb, which binds to sulfatide on the cell surface (not shown). Cells which were positive for sulfatide also bound sHIgM22 (A) and sHIgM14 (B). Although both antibodies bind to the surface of oligodendrocytes, the sHIgM22 antibody actively promotes remyelination, while the sHIgM14 antibody does not. Magnification X400.
other groups has demonstrated the principle that oligodendrocyte-specific antibodies can cause biochemical and morphologic changes in these cells. Dyer and co-workers have reported that several different antibodies directed against oligodendro-cyte surface epitopes, including antibodies to galactocerebroside (GalC), sulfatide and myelin/ oligodendrocyte-specific protein (MOSP), can induce changes in the organization of oligodendroglial membrane sheets and in the structure of the oligo-dendrocyte cytoskeleton.30-32 These changes in cellular structure were preceded, and probably triggered, by antibody-induced calcium influx.33-35 Antibody-mediated calcium influx may therefore play an important role in the regulation of oligodendrocyte function and could conceivably play a role in antibody-induced remyelination as well. In addition, Bansal and co-workers have reported that antibodies directed against oligodendrocyte surface antigens can either enhance the rate and extent of oligoden-drocyte differentiation,36 or can inhibit the differentiation of oligodendrocyte progenitors,37,38 depending upon the specificity of the antibody.
Antibodies might also work to enhance myelin repair through more indirect mechanisms. An attractive hypothesis is that by binding to damaged oligo-dendrocytes and myelin, there may be opsonization and clearing of CNS debris by macrophages, thus allowing for the normal process of remyelination to ensue. The remyelination-promoting antibodies are all of the IgM isotype, and one of the properties of IgM antibodies is their efficient activation of complement. DeJong and Smith recently demonstrated that complement is a necessary factor for maximal efficiency of myelin phagocytosis by cultured macrophages and have proposed that one important effect of complement is to fragment myelin debris, making phagocytosis more efficient.39 Large numbers of macrophages are often observed in demyelinated lesions, and phagocytosis of myelin debris may be an important prerequisite for efficient remyelination. Enhanced complement fixation following the binding of myelin debris by remyeli-nation-promoting IgM antibodies may play a role in this process. Recent studies in culture have also demonstrated that treatment with polyclonal human immunoglobulins (IVIg) can act to stimulate the invasion of macrophages into injured nervous tissue and can enhance the phagocytosis and clearance of damaged myelin.40
Finally, remyelination-promoting antibodies have been shown to have immunomodulatory effects. A T-cell-mediated immune response has been shown to prevent spontaneous remyelination in chronic TMEV-infected SJL mice, and enhanced remyelina-tion due to antibody-mediated suppression of an inhibitory immune response is another potential mechanism of action of remyelination-promoting antibodies. We have previously demonstrated that in chronic TMEV-infected mice, SCH94.03 treatment results in a 2-3-fold reduction in the number of CD4+ and CD8+ T-cells infiltrating the CNS, and also inhibits humoral antibody responses directed against several different immunizing antigens.41 The observation that SCH94.03 has immunomodulatory activity is supported by its strong reactivity to dendritic cells of peripheral lymphoid organs, which may be involved in lymphocyte activation.41
We have also demonstrated an effect of SCH94.03 treatment on established relapsing EAE in SJL mice. EAE was induced by the adoptive transfer of myelin basic protein peptide-specific T-cells, and antibody treatment was initiated after recovery from the initial episode of clinical disease. Treatment with SCH94.03 reduced by half the percentage of mice that suffered clinical relapse, and prolonged relapse onset by an average of 6 days in those mice that did relapse.42 The observation that SCH94.03 suppresses CNS inflammation in both the TMEV and EAE models argues strongly for a role for these antibodies as immunomodulatory agents.
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