Islet transplantation is an intriguing therapeutic platform for treatment of T1D but will not become a widespread clinical reality until it can be proven that the islet product can safely provide a substantial therapeutic benefit on a consistent basis in an efficient manner. To address these challenges the Clinical Islet Transplant (CIT) Consortium was formed. The aim of the Continuation Award is to complete the existing CIT islet transplant studies to substantially improve treatment of T1D and obtain licensure of the human islet product. Three study protocols have been developed. The Specific Aims as they relate to each protocol are: 1. To determine the safety and efficacy of peri-transplant administration of deoxyspergualin (DSG) on the engraftment and function of pancreatic islet transplants in T1D patients (CIT Protocol 03). 2. To determine the safety and efficacy of a steroid-free, tacrolimus sparing immunosuppressive protocol in T1D patients receiving pancreatic islet transplants (CIT Protocol 07). 3. To determine the efficacy of islet transplantation in T1D kidney allograft recipients (CIT Protocol 06). To achieve the aims of CIT-03, Northwestern will participate in a prospective, randomized, three-center, open-label trial assessing the safety and efficacy of DSG on post-transplant islet function in subjects with long-standing TID that is refractory to intensive insulin therapy. The three centers in the study. Northwestern, Minnesota and UCSF, will collectively transplant 20 recipients using DSG (ClT-03) and contribute 12 of the 48 recipients into the CIT-07 protocol that is the registration trial component and also serves as the control group for the DSG study. Northwestern will transplant a minimum of 10-11 subjects in CIT-03/-07, and 4 patients in CIT-06. To expedite the completion of these trials, Northwestern aims to transplant 4 subjects under ClT-03 and 2 subjects under ClT-07 before the conclusion of the current grant award. Northwestern has met the CIT consortium site qualification criteria for quality islet isolation standards using the CIT batch record, and for clinical experience based on volume of activity and quality outcomes. Site activation has been achieved. To date, Northwestern has transplanted 3 patients, all randomized to the ClT-03 study. Northwestern is well positioned to continue as an active participant in the CIT clinical trials. RELEVANCE (provided by the applicant): Type 1 diabetes (T1D) afflicts nearly 2 million people in the United States, most of them children or young adults, and untreated, it is a fatal disease. Insulin therapy can be administered, but does not result in good health-related quality of life and can lead to diabetic retinopathy and nephropathy, which are the most common causes of adult blindness and kidney transplant respectively. The goal is to achieve insulin independence for Type 1 diabetes patients with Islet Transplantation, improving their overall quality of life and disease management with less risk than whole pancreas transplant.