STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

大规模胰岛置换策略

• 批准号: 8172390
• 负责人: THOMAS C PEARSON
• 金额: $ 5.48万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8172390
• 关键词: Allogenic; Allografting; Anatomic Sites; Animals; Antibodies; Blood Glucose; Clinic; Computer Retrieval of Information on Scientific Projects Database; Data; Diabetes Mellitus; Fasting; Funding; Future; Graft Survival; Grant; Immunosuppressive Agents; Institution; Islets of Langerhans Transplantation; LEA29Y; Macaca mulatta; Modeling; Monoclonal Antibodies; Mus; Muscle; Pathway interactions; Recombinants; Regimen; Reporting; Research; Research Personnel; Resources; Sirolimus; Source; Streptozocin; TNFRSF5 gene; Testing; Translations; Transplantation; United States National Institutes of Health; base; basiliximab; clinically relevant; cohort; islet; pre-clinical; research study; success; trapezius muscle

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. During the reporting period, we have shown that targeting the CD28/CD80/CD86 and CD40/CD154 costimulatory pathways, by using LEA29Y and Chi220, prolongs allograft survival in rhesus macaques. Based on these results, we investigated the effects of CTLA4Ig and 3A8, which likewise inhibit the CD28/CD80/CD86 and CD40/CD154 pathways, respectively. All recipients in this cohort had immediate allograft function with normalization of fasting blood sugars and prolonged allograft survival, showing costimulation blockade-based regimens continue to yield success in islet transplantation. After transitioning to a new diabetes induction model with the use of streptozocin, experiments began to determine the optimal islet mass and anatomic site for islet transplantation. One animal was transplanted with15,000IE/kg of allogeneic islets intramuscularly into the trapezius and latissimus dorsi muscles with moderate success. In this report period, no further islet mass or anatomic site experiments have been done due to the desire for a more optimal biologic immunosuppressive regimen. In search of a more clinically relevant, less toxic regimen, anti-LFA-1 mAb and belatacept alone, resulted in immediate reversal of diabetes and islet survival for 367, 223, 373, 73 and 269 days. This biologic regimen promises to be a clinically relevant, tolerable regimen with potential for translation into the clinic. Additionally, we have further investigated the use of 3A8, a non-depleting mouse monoclonal antibody targeting CD40. Animals transplanted allogeneic islets under cover of 3A8, basiliximab and sirolimus had graft survivals of 155, 312, 208, 120, 45 days, establishing the potential of blocking the CD40 pathway in a non-depleting fashion in transplantation. Future plans include the testing of recombinant anti-CD40 antibodies for better characterization of CD40-blockade in our islet model and transplantation, and using anti-CD40-based biologic regimens to establish preclinical data for translation into the clinic.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目和 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 对于中心来说，它不一定是研究者的机构。 在报告期内，我们已经证明，通过使用 LEA29Y 和 Chi220，针对 CD28/CD80/CD86 和 CD40/CD154 共刺激途径，可以延长恒河猴的同种异体移植物存活期。基于这些结果，我们研究了 CTLA4Ig 和 3A8 的作用，它们同样分别抑制 CD28/CD80/CD86 和 CD40/CD154 途径。该队列中的所有受者均具有即刻的同种异体移植功能，空腹血糖正常化，同种异体移植物存活时间延长，这表明基于共刺激阻断的方案在胰岛移植中继续取得成功。 在使用链佐星转变为新的糖尿病诱导模型后，实验开始确定胰岛移植的最佳胰岛质量和解剖部位。将15,000IE/kg的同种异体胰岛肌肉注射到一只动物的斜方肌和背阔肌中，取得了一定的成功。在本报告期内，由于需要更优化的生物免疫抑制方案，尚未进行进一步的胰岛质量或解剖部位实验。为了寻找更具临床相关性、毒性较小的治疗方案，单独使用抗 LFA-1 mAb 和贝拉西普可立即逆转糖尿病，并且胰岛存活期分别为 367、223、373、73 和 269 天。 这种生物疗法有望成为一种临床相关的、可耐受的疗法，并有可能转化为临床。此外，我们还进一步研究了 3A8（一种靶向 CD40 的非耗竭小鼠单克隆抗体）的用途。在3A8、巴利昔单抗和西罗莫司覆盖下移植同种异体胰岛的动物的移植物存活期为155、312、208、120、45天，建立了在移植中以非耗尽方式阻断CD40途径的潜力。 未来的计划包括测试重组抗 CD40 抗体，以更好地表征我们的胰岛模型和移植中的 CD40 阻断，并使用基于抗 CD40 的生物方案建立临床前数据以转化为临床。