Living related donor islet transplantation in the haplotype identical chimeric rhesus macaque

Islet allograft transplantation has the potential to reverse type 1 diabetes if maintenance immunosuppression is provided indefinitely. The development of a protocol to achieve durable islet allograft function without the need for indefinite, immunosuppression remains a research goal of significant interest. This study describes a hematopoietic stem cell (HSC), nonhuman primate (NHP), preclinical, transplant protocol that takes steps toward reaching that goal. This protocol involves living donor hematopoietic stem cell transplantation followed by donor specific islet transplantation to reverse diabetes. A low intensity preconditioning regimen with low-dose total body irradiation (TBI) and cyclophosphamide was well tolerated. Antibody induction and temporary immunosuppression resulted in high levels of HSC engraftment confirmed by short tandem repeat (STR) DNA markers. The hematopoietic stem cell transplantation (HSCT) was completed on day 75. Recipient diabetes induction was performed on day 96. Donor specific islet transplantation without ongoing immunosuppression was performed on day 126. One chimeric recipient maintained islet allograft function for 92 days without ongoing immunosuppression. A recipient that failed to engraft donor stem cells lost islet allograft function at 14 days. The islet allograft failed immediately in a chimeric recipient documented to have developed donor specific antibodies. Durable allograft tolerance was not achieved in any recipient using this protocol. However HSCT protocols modified to achieve T-regulatory cell enrichment with could be evaluated using this preclinical model. This preclinical model could also be used to investigate the immunologic mechanisms involved in donor specific allograft tolerance.