Improving Porcine Islet Function and In Vivo Survival with Lisofylline

描述（由申请人提供）：用于治疗I型糖尿病（T1D）的封装猪（xeno）胰岛移植目前被认为是胰岛移植的下一代产品。组织短缺的问题很容易通过使用猪胰岛来解决，然而，在各种体内模型中，影响移植物存活的免疫成分还没有得到很好的定义。在没有免疫抑制剂的情况下，将海藻酸盐包裹的猪岛移植到大鼠和非人灵长类动物的腹膜中会出现大量的免疫障碍。我们MicroIslet， Inc.正在积极研究与早期排斥有关的免疫事件。有趣的是，我们在灵长类动物身上的研究表明，短暂使用传统的t细胞特异性免疫抑制剂，如FK506和雷帕霉素，可以延长移植物的存活时间，并减少50-60%的胰岛素需求。为了优化移植物的长期功能，我们计划研究一种合成的、非糖尿病性的、抗炎症的甲基黄嘌呤分子，称为异茶碱（LSF），是否会在体内对被封装的猪胰岛移植的存活提供显著的有益影响。

DESCRIPTION (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 addressed 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 porcine 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 transient 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 synthetic, 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 gene 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 term 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 the 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.