BACKGROUND AND UNSOLVED ISSUES. In principle, treatment for type-1 diabetes and many cases of type-2 diabetes, lies in the possibility of finding a beta cell mass replacement capable of performing two essential functions: assessing blood sugar levels and secreting appropriate levels of insulin in the vascular bed. Currently, the only available clinical therapy capable of restoring beta cell mass in diabetic patients is the allogeneic/autologous transplantation of beta cells. Despite advances in recent years the somatic cell therapy is still problematic. Our project focuses on creating conditions that favour beta cell expansion and survival in transplanted and native environments STARTING HYPOTHESIS AND MAIN RESULTS. The somatic cell therapy for type 1 diabetes is a great platform to address mechanistic questions regarding type-1 diabetes. In the last years we were able to study the impact of beta cell challenge to the immune status of the patient and the efficacy of immunotherapeutics and their ability to control allogeneic and autoimmune responses. The results of these studies demonstrate (i) that survival of both syngeneic and allogeneic islet grafts in the liver is sub-optimal, (ii) that inflammatory reaction play a relevant role for the survival and function of islets after transplantation, (iii) that the actual immunosuppressive regimens do not control efficiently both allogeneic and autoimmune response. CONCLUSIONS AND FUTURE PLANS. To obtain the long term replacement of beta cells in patients with diabetes we propose to: (I) study bone marrow as site for islet transplantation, (II) develop novel islet survival strategies by modulating inflammation specifically inhibiting pathways involving CCL2 or IL-8, (III) Improve islet transplantation outcome by cotransplantation of islets and feeder cells using mesenchymal stem cells, (IV) determine mechanisms of islet autoantigen immunization and destruction (V) to identify a renewable source of cells to be used to increase the transplantable beta cell mass.