This project aimed to cure diabetic nephropathy by utilizing a composite islet-kidney combined with hematopoietic cell transplantation. Over a three-year period, the goal of a three-step progressive improvement in the immune tolerance-inducing immunosuppressive therapy was achieved. Although we have exceeded 200 days survival of composite islet-kidney grafts with first-generation immunosuppression, further efforts are required to reduce drug-induced islet toxicity and improve donor chimerism. The second step demonstrated evidence of BM engraftment at day 37 and rejection free islet-kidney grafts, and the third step further improved % and duration of donor chimerism. With the establishment of the leukapheresis procedure, we have achieved peripheral chimerism for more than 30% over 6 weeks following transplantation, as well as further bone marrow chimerism.