RAPAMYCIN+IL-10-BASED TREATMENT FOR THE CURE OF TYPE 1 DIABETES: FROM MOUSE TO MAN

Type 1 diabetes (T1D) is the result of a T-lymphocyte–dependent autoimmune process that specifically destroys the insulin-secreting b-cells of the pancreas. Blockade of autoaggressive T cells and re-establishment of tolerance to the b-islets is fundamental for the definitive cure of autoimmune diabetes. Immunological tolerance can be achieved by the induction of a subset of T cells, named T regulatory (Tr) cells, that specifically suppress the effector T cells reacting against pancreatic b-islets, while leaving the rest of the immune system intact. The naturally occurring CD4+CD25+ Tr cells and the T regulatory type 1 cells (Tr1) have been involved in preventing the development of autoimmune diseases in several animal models. Therefore, protocols aimed at reverting T1D should consider both blockade of autoaggressive T cells and induction of long-lasting Tr cells.Recent results generated in our laboratory demonstrate that prolonged treatment with an immunosuppressant, rapamycin, and an immunomodulatory cytokine, IL-10, blocks diabetes development in pre-diabetic NOD mice through the induction of CD4+CD25+ Tr cells in the pancreas, mediated by rapamycin, and the generation of Tr1 cells in the spleen, mediated by IL-10.In the present proposal we intend to define the best rapamycin+IL-10-based protocol that induces immunological tolerance and therefore can prevent onset and progression of autoimmune diabetes in NOD mice. In addition, we will investigate in vitro the effects of rapamycin+IL-10 on murine and human Tr cells.Results from this study will allow the design of a protocol able to halt autoimmune diabetes and re-establish self-tolerance, which can be applied to T1D patients. Furthermore, we will gain important new insights in the biology of Tr cells and their ability to interfere with autoimmune diseases.