Improving Porcine Islet Function and In Vivo Survival with Lisofylline

用利索茶碱改善猪胰岛功能和体内存活率

• 批准号: 7483549
• 负责人: INGRID STUIVER
• 金额: $ 2.02万
• 依托单位: MICROISLET, INC.
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-05-01 至 2010-09-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7483549
• 关键词: Address; Alginates; Animals; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Apoptosis; Autoimmune Diseases; Blood; Blood Glucose; Clinical Trials; Diabetes Mellitus; Disease Progression; Dose; Effectiveness; Encapsulated; Event; FK506; Family suidae; Funding; Genetic Transcription; Glucose tolerance test; Graft Survival; Human; Immune; Immune response; Immunosuppressive Agents; Implant; In Vitro; Inbred NOD Mice; Inflammatory; Insulin; Insulin-Dependent Diabetes Mellitus; Interleukin-12; Islets of Langerhans Transplantation; Lisofylline; Longevity; Measurement; Measures; Mediating; Microcapsules drug delivery system; Monitor; Mus; Non obese; Numbers; Onset of illness; Outcome; Peptides; Performance; Peritoneum; Phase; Primates; Principal Investigator; Process; Public Health; Rattus; Reaction; Reading; STAT4 protein; Serum; Signal Transduction; Sirolimus; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; Sus scrofa; Switch Genes; System; T-Lymphocyte; Technology; Testing; Therapeutic; Time; Tissues; Transplantation; United States National Institutes of Health; Upper arm; Week; Work; Xanthines; Xeno; concept; cytokine; day; diabetic; exenatide; graft function; implantation; improved; in vivo; in vivo Model; interest; interleukin-12 receptor; islet; mimetics; next generation; nonhuman primate; pre-clinical; programs; response; size; small molecule; volunteer; xanthine

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.

描述（由申请人提供）：用于治疗 I 型糖尿病（T1D）的封装猪（异种）胰岛移植目前被认为是下一代胰岛移植产品。使用猪胰岛可以轻松解决组织短缺的问题，但是在各种体内模型中损害移植物存活的免疫成分尚未明确。在没有免疫抑制剂的情况下，将藻酸盐封装的猪胰岛移植到大鼠和非人灵长类动物的腹膜中时，会出现大量的免疫障碍。我们 MicroIslet, Inc. 正在积极研究早期排斥反应中涉及的免疫事件。有趣的是，我们在灵长类动物中的研究表明，短暂使用传统 T 细胞特异性免疫抑制剂（如 FK506 和雷帕霉素）可延长移植物存活时间，并减少 50-60% 的胰岛素需求。在我们努力优化长期移植物功能的过程中，我们计划研究一种合成的、非糖尿病性的、抗炎的甲基黄嘌呤分子，称为利索茶碱（LSF），是否会对体内封装的移植物的存活产生显着的有益作用。猪胰岛移植。 通过称为“信号转导子和转录激活子 4”(STAT 4) 的主基因开关的 IL-12 信号通路对于介导免疫反应的早期阶段以及自身免疫性疾病至关重要。 STAT 4 的激活导致产生高度促炎细胞因子的基因转录。 LSF 是一种小分子，参与阻断 IL-12 受体依赖性 STAT 4 的激活。体内和体外研究均表明，LSF 可以保护胰岛免受细胞因子诱导的细胞凋亡并增强功能。用 LSF 预处理胰岛可减少糖尿病动物达到正常血糖所需的移植物大小。就自身免疫性疾病而言，STAT 4 缺陷的非肥胖糖尿病 (NOD) 小鼠不会发展为自发性糖尿病。 LSF 的短期全身给药可阻止（糖尿病）NOD 的疾病发作和疾病进展。我们有兴趣探索 LSF 对体内封装猪胰岛的功能增强、细胞保护和免疫调节作用，如以下三个具体目标所述。将使用自发性糖尿病 NOD 小鼠来比较植入有和没有 LSF 的藻酸盐封装的猪胰岛的免疫反应。将评估 LSF 的 3 种不同应用对减少早期体内免疫反应的有效性。公共健康相关性：MicroIslet, Inc 有兴趣探索 LSF 的瞬时利用，或在我们的工艺中 LSF 与肠促胰素模拟物（如 Exendin 4）的组合可能会增强我们的产品、封装的猪胰岛的性能，并展示长期的移植功能和I 型糖尿病最佳治疗的生存期。