Immunosuppression

A fundamental question in transplantation is whether immunosuppression is necessary in order to permit host tolerance of the graft. The brain has been considered to be an immunologically privileged site, but immune rejection can still occur even following transplantation of autografts (Fisher and Gage, 1993; Drucker-Colin and Verdugo-Diaz, 2004). While intracerebral grafts can survive in the absence of immuno-suppression, differences in the expression of major and minor histocompatability antigens between graft and host can result in a long-term inflammatory response with macrophage and microglial activation and upregulation of immunological markers (Duan et al., 1993; Shinoda et al., 1995; 1996; Baker-Cairns et al., 1996). Such immune reactions could be detrimental to graft survival and function, and are likely relevant to human transplantation. Indeed, evidence of some degree of an immune response was seen in post-mortem studies of patients in each of the double-blind trials. In addition, we have previously demonstrated dense HLA-DR immunostaining and numerous pan macrophages, T-cells, and B-cells in otherwise normal appearing graft deposits, 18 months following fetal nigral transplantation (Kordower et al., 1997). Further, Freed et al. did not use immunosuppression and had much less survival of transplanted cells than did Olanow et al. who employed cyclosporine for 6 months (Kordower et al., 1995; 1996; Freed et al., 2001; Olanow et al., 2003). Indeed, in the latter group it was suggested that an immune response may have limited the clinical benefit of fetal nigral transplantation, as benefits deteriorated following withdrawal of cyclosporine and there was evidence of increased CD45 staining in grafter regions at post-mortem (Olanow et al., 2003). These studies each used solid tissue grafts, and it has been suggested that solid grafts are more likely to generate an immune response as the blood vessels within the graft are of donor origin and likely to express major histocompatability type 1 antigens which are intensely immunogenic (Baker-Cairns et al., 1996). In this regard, the Lund group used suspension grafts and a "cocktail" of three immunosup-pressive agents, and reported long-lasting benefits with the ability to stop levodopa in some patients (Wenning et al., 1997; Piccini et al., 2000). Thus, current evidence suggests that long-term immunosuppres-sion might be desirable in future transplant regimens.

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