The effect of immunosuppressive protocols on spontaneous CNS remyelination following toxin-induced demyelination

Glial cell transplantation is a potential therapy for human demyelinating disease, though obtaining large numbers of human myelinating cells for transplantation remains a major stumbling block. Autologous transplantation is currently not possible, since the adult human CNS is not a good source of oligodendrocyte precursors, and long-term immunosuppression of engrafted allogeneic or xenogeneic cells is therefore likely to be necessary. Immunosuppressive drugs may need to be used in situations where more recent, active areas of demyelination are undergoing endogenous remyelination. It is therefore pertinent to establish the extent to which immunosuppressive protocols will suppress spontaneous remyelination. In order to investigate this issue, we created demyelinating lesions in the spinal cord of adult rats and compared the extent of remyelination in animals receiving different immunosuppressive treatments. In animals given only cyclosporin A, there was no difference in the extent of either Schwann cell or oligodendrocyte remyelination of ethidium bromide-induced demyelinating lesions. However, in animals given cyclophosphamide, either alone or in combination with cyclosporin, there was a significant reduction in the extent of oligodendrocyte-mediated remyelination. These results demonstrate that cyclophosphamide is deleterious to oligodendrocyte remyelination and for this reason should be used with caution in patients with demyelinating disease.