Improving Porcine Islet Function and In Vivo Survival with Lisofylline
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AbstractDESCRIPTION (provided by applicant): Encapsulated porcine (xeno) islet transplantation for the treatment of Type I Diabetes (T1D) is currently considered to be the next generation product for islet transplantation. The issue of tissue shortage is easily ad dressed by the use of porcine islets, however the immune component that compromises graft survival in various in vivo models has not been readily defined. A significant number of immunological obstacles arise when transplanting alginate encapsulated porcin e islets into the peritoneum of rats and non-human primates in the absence of immunosuppressants. We at MicroIslet, Inc. are actively studying the immunological events involved in the early rejection. Interestingly, our work in primates indicates that tran sient use of conventional T-cell specific immunosuppressants such as FK506 and Rapamycin confers prolonged graft survival and a 50-60% reduction in insulin requirements. In our effort to optimize long-term graft function we plan to study whether a syntheti c, non-diabetogenic, anti- inflammatory methyl-xanthine molecule, termed lisofylline (LSF), will provide a significant beneficial effect in vivo, on the survival of encapsulated porcine islet transplantation. IL-12 signaling path via the master gen e switch termed signal transducers and activators of transcription 4 (STAT 4) is critical for mediating early phases of immune reaction as well as autoimmune diseases. The activation of STAT 4 results in the transcription of genes that produce highly pro -inflammatory cytokines. LSF is a small molecule that participates in blocking IL-12 receptor dependent activation of STAT 4. It has been demonstrated both in vivo and in vitro studies that LSF can protect islets from cytokine induced apoptosis as well as enhance function. Pretreatment of islets with LSF reduces the graft size necessary to achieve normoglycemia in diabetic animals. In terms of autoimmune disorders, STAT 4 deficient non-obese diabetic (NOD) mice do not develop spontaneous diabetes. Short ter m systemic administration of LSF blocks disease onset and disease progression in (diabetic) NODs. We are interested in exploring the function enhancing, cytoprotective and immunomodulatory effects of LSF on encapsulated porcine islets in vivo as described in the following three Specific Aims. Spontaneously diabetic NOD mice will be used to compare the immunological response to implantation of alginate encapsulated porcine islets with and without LSF. The effectiveness of 3 different applications of LSF on t he reduction of the early in vivo immune response will be assessed. PUBLIC HEALTH RELEVANCE: MicroIslet, Inc is interested in exploring the transient utilization of LSF or the combination of LSF and an incretin mimetic such as exendin 4 in our process may enhance the performance of our product, encapsulated porcine islets, and demonstrate prolonged graft function and survival for the optimal treatment of type I diabetes.
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