Different methods of immunosuppresion do not prolong the survival of human cord blood-derived neural stem cells transplanted into focal brain-injured immunocompetent rats.

Cerebrovascular diseases are the leading cause of severe disability worldwide, with an enormous financial burden for society. There is growing evidence that stem cell-based therapy may positively influence recovery from stroke. Cord blood is an attractive source of ontogenetically young, yet safe, stem cells. Conceptually, preclinical studies in which donor cells were of human origin have been the most valuable, and thus, it is likely that these cells will be used in clinical trials. Unfortunately, immunological barriers impede discordant xenotransplantations. We have previously observed acute rejection of cord blood derived neural stem cells (HUCB-NSC) after transplantation to the brains of intact animals. Since it was reported recently that a brain lesion may actually improve the chances of graft survival, in this study, we used infarcted animals as graft recipients. In ongoing studies, we tested three immunosuppressive regimes: group I received cyclosporine A (CsA: 10 mg per kg i.p.); group II received a triple-drug therapy (CsA: 10 mg per kg i.p., azathioprine: 5 mg per kg i.p., and methylprednisolone: 1.5 mg per kg i.m.); group III included rats that were formerly desensitized with HUCB, group IV had not undergone immunosuppression. Animals were sacrificed at five time-points: 1, 3, 7, 14, and 21 days post-transplantation to evaluate graft survival and the time-course of immunological response. We observed a gradual decrease in the number of transplanted cells, with complete disappearance by day 14, surprisingly, with no difference among the experimental groups. The involvement of the innate immune system in the process of graft rejection dominated over an adaptive immunoresponse, with the highest activity on day 3, and subsequent fading of immune cell infiltration. In this work, we have shown that none of our immunosuppressive strategies proved adequate to prevent rejection of human stem cell grafts after transplantation into immunocompetent animals.