Preclinical in vivo assessment of a combination of protein and cell therapies to prevent human islet transplant rejection as a cure for Type 1 diabete

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Type 1 diabetes (T1DM) is an autoimmune disease in which the beta-cells of the pancreas are destroyed by autoreactive lymphocytes and insulin is no longer produced. The only clinically acceptable treatment for T1DM is insulin replacement by daily injection of the hormone. This treatment makes T1DM very difficult to control, with the result that patients are exposed to high blood glucose and risk of diabetic complications and/or intermittent low blood glucose that can cause unconsciousness, fits and even, albeit rarely, death. Transplantation of pancreatic islets became an alternative strategy to whole pancreas transplantation due to the advantage of a relatively non invasive technique and to the low risk of surgical complications. However, transplanted islets are subjected to progressive loss, with most of the patients requiring exogenous insulin within 2 years post-transplant. Therefore, there is an urgent need for improvements in islet transplantation. This project, by establishing a new preclinical animal model, will provide novel insights into the mechanisms of human islet graft rejection in vivo and will offer a perfect platform for the development of new therapies in the prevention of islet graft rejection. We have already demonstrated that: 1. A recombinant cytoprotective protein (APT070) can protect kidney grafts from complement-mediated post-ischaemic damage; 2. In vitro expanded human regulatory T cells (Tregs) can prolong human skin allograft survival in immunodeficient mice reconstituted with PBMC. 3. In a similar model to the one proposed in this project, ex-vivo expanded human Tregs can delay human islet rejection. 4. Complement influences human T cell responses to antigenic stimulation. Indeed APT070 is already in Phase 1 clinical trial in kidney transplantation and adoptive transfer of Tregs has been already applied successfully in bone marrow transplantation to prevent Graft versus Host Disease. We hypothesize that combining Treg injection with pre-treatment of islets with cytoprotective proteins targeting complement activation will successfully induce indefinite survival of transplanted allogeneic islets. To test this hypothesis, we will 1) further refine the humanised mouse model by using immunodeficient mice transgenic for human MHC molecules; 2) study the immune responses (innate and adaptive) to allogeneic islets in vivo; 3) investigate the therapeutic use of Tregs in combination with the cytoprotective therapeutic protein in preventing rejection of human islets.The results from the proposed study will provide new insights into establishing the optimal therapy to achieve indefinite survival of islet cells in the cure of Type I diabetes.