STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

大规模胰岛置换策略

• 批准号: 8172388
• 负责人: CHRISTIAN P LARSEN
• 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/8172388
• 关键词: Allogenic; Anatomic Sites; Animals; Antibodies; Clinic; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Data; Diabetes Mellitus; Funding; Future; Graft Survival; Grant; Immunosuppressive Agents; Institution; Modeling; Monoclonal Antibodies; Mus; Pathway interactions; Primates; Recombinants; Regimen; Reporting; Research; Research Personnel; Resources; Sirolimus; Source; TNFRSF5 gene; Testing; Translations; Transplantation; United States National Institutes of Health; anti-LFA-1 monoclonal antibody; base; basiliximab; clinically relevant; islet; pre-clinical; research study

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. 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, primates were transplanted allogeneic islets under cover of anti-LFA-1 monoclonal antibody-based therapy with very promising results. Anti-LFA-1 has proven to be a very potent immunosuppressant in our preclinical islet transplant model, making the case for its use in clinical trials. More promising though has been the recent use of a purely biologic regimen, anti-LFA-1 mAb and belatacept alone, resulting 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 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。子项目及 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。 在本报告期内，由于需要更优化的生物免疫抑制方案，没有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，灵长类动物在抗 LFA-1 单克隆抗体疗法的掩护下移植了同种异体胰岛，取得了非常有希望的结果。在我们的临床前胰岛移植模型中，抗 LFA-1 已被证明是一种非常有效的免疫抑制剂，这为其在临床试验中的使用提供了理由。不过，更有希望的是最近使用纯生物疗法、抗 LFA-1 单克隆抗体和贝拉西普单独治疗，导致糖尿病立即逆转，胰岛存活时间分别为 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，我们还研究了 3A8（一种靶向 CD40 的非耗竭小鼠单克隆抗体）的使用。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。