Haplotype matching is not an essential requirement to achieve remyelination of demyelinating CNS lesions

Abstract

Transplantation of oligodendrocyte precursor cells (OPCs) results in efficient remyelination in animal models of demyelination. However, the experiments so far undertaken have not addressed the need for tissue-type matching to achieve graft-mediated remyelination. Examination of MHC expression (main determinant of allograft rejection) by OPCs showed nondetectable levels under standard culture conditions and upregulation of MHC Class I expression only upon exposure to interferon gamma. We therefore hypothesized that MHC matching of OPC grafts may not be crucial to achieve transplant-mediated remyelination. Transplant experiments performed using a nonself repairing toxin-induced demyelination model showed that, similarly to allogeneic neurons, survival of allogeneic oligodendrocyte lineage cells is influenced by donor-host haplotype combination and graft composition. Transplantation of allogeneic mixed glial cell cultures resulted in remyelination failure by 1 month postengraftment due to a rejection response targeting both myelinating oligodendrocytes and OPCs, suggesting that inflammation-induced upregulation of OPC MHC I expression results in susceptibility to cytotoxic T cell attack. In contrast, remyelination persisted for at least 2 months following transplantation of OPC-enriched cultures whose overall MHC expression level was significantly decreased. While OPC-enriched preparations elicited delayed type hypersensitivity responses in hosts sensitized to alloantigens, allografting of such preparations into a central nervous system demyelinating lesion did not result in recipient priming. We conclude that while allografted oligodendrocyte lineage cells become targets of a graft rejection response once this response has been initiated, transplantation of OPC-enriched preparations can evade priming against alloantigens and graft rejection. This finding indicates that close tissue matching may not be an essential requirement for successful transplant-mediated remyelination.