Search

Protection of transplanted pancreatic islet grafts in recipients with autoimmune diabetes depends on the suppression of autoimmune recurrence and allogeneic rejection. The aim of this study was to investigate the efficiency of viral IL-10 gene delivery in the prevention of autoimmune recurrence following islet transplantation. We evaluated the effectiveness of a systemically delivered adeno-associated viral vector (AAV vIL-10) carrying viral IL-10 in protecting islet engraftment. We observed significant prolongation of graft survival after treatment with AAV vIL-10 when using islets from donors lacking autoimmunity. We found that the mechanism of vIL-10-mediated protection was associated with suppression of T cell activation and that donor immune cells that were simultaneously transferred with the islet grafts could induce autoimmune recurrence. AAV vIL-10 gene transfer suppressed previously activated T cells and protected grafted islets from autoimmune-mediated destruction. We conclude that vIL-10 can regulate autoimmune activity and that transfer of its gene may have potential for therapeutic islet transplantation.

Signal transducers and activators of transcription (STAT) proteins are activated in response to many cytokines, growth factors and hormones. STAT4 mediates IL-12 signaling and regulates T helper 1 (Th1) cell differentiation. Both IL-12 and Th1 cell activation participate in the development of autoimmune diabetes. In this study, we investigated the role of STAT4 in autoimmune diabetes. We crossbred Stat4 deficient (Stat4-/-) mice with nonobese diabetic (NOD) mice to generate the Stat4-/- NOD model. In Stat4-/- NOD mice, serum levels of both IFN-gamma and IL-2 were significantly reduced as compared to the controls. Insulin secretion in pancreatic islets was preserved in Stat4-/- NOD mice. Significantly, disruption of Stat4 activation completely prevented the development of spontaneous diabetes in NOD mice. This study reveals the important role of STAT4 in autoimmune diabetes pathogenesis.

FTY720 is a novel immune regulatory drug derived from the fungal sphingosine analog ISP-1 (myriocin). FTY720 causes a redistribution of lymphocytes from circulation to secondary lymphoid tissues. Type 1 diabetes is an autoimmune disorder caused by cellular-mediated destruction of insulin-producing pancreatic β cells in the islets of Langerhans. Indeed, local infiltration of islets by mononuclear cells is the hallmark of Type 1 diabetes. Based on both FTY720’s action and the involvement of cellular infiltration in the disease progression, we tested FTY720 for its ability to prevent autoimmune diabetes in diabetes-prone, nonobese diabetic (NOD) mice. We found that treatment with FTY720 completely prevented NOD mice from developing autoimmune diabetes. The FTY720-treated animals showed both reduced numbers of circulating lymphocytes and sharply diminished cellular infiltration of pancreatic islets. These results suggest that FTY720 may be effective in prevention of autoimmune diabetes or in slowing its progression.

Autoimmune-mediated cytotoxicity may cause pancreatic islet transplant failure, leading to recurrent diabetes. Protection of islet grafts depends on immunosuppressive control, which may also prevent autoimmune recurrence of diabetes. In this study, we compared the survival of syngeneic islet transplants using different strains of donor mice. We observed extended functional survival in the islet grafts from donors lacking the genetic background and potential of autoimmunity. Without immunosuppression, the islet grafts of NOR and immune-deficient NOD. Scid donors functioned up to 3 weeks in syngeneic islet transplants compared to 3-day survivals with the grafts from NOD donors. T-cell proliferation and activation markers, CD44 and CD69, were upregulated in NOD donors, suggesting that T-cell activation had occurred prior to pancreas procurement. Systemic delivery of a recombinant adenoassociated viral vector (AAV) encoding the viral (vIL-10) IL-10 gene (AAV vIL-10) in NOD recipients protected syngeneic islets from autoimmune destruction. Alternatively, pretreatment of NOD donor mice with AAV vIL-10 prolonged islet graft survival in untreated NOD recipients. Both studies indicate the effectiveness of vIL-10 gene therapy in autoimmune regulation. These results suggest that a donor factor may exist in autoimmune-prone donors. Therefore, autoimmune recurrence of diabetes may result from donor immune cells transferred during islet transplantation. The AAV vIL-10 gene therapy suppressed previously activated donor T cells and protected the grafted islets from autoimmune-mediated destruction.