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.

这个子项目是许多利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 在本报告期间，由于需要更佳的生物免疫抑制方案，未进行进一步的胰岛质量或解剖部位实验。为了寻找临床相关性更高、毒性更低的治疗方案，在基于抗LFA-1单克隆抗体的治疗的掩护下，对灵长类动物移植同种异体胰岛，结果非常有希望。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，这使得它在临床试验中的应用成为可能。更有希望的是最近使用的纯生物方案，抗LFA-1单克隆抗体和贝拉西普单独，导致糖尿病和胰岛存活367，223，373，73和269天的立即逆转。这种生物治疗方案有望成为临床相关、可耐受的治疗方案，并有可能转化为临床治疗。 此外，我们还研究了3A 8（一种靶向CD 40的非消耗性小鼠单克隆抗体）的使用。在3A 8、巴利昔单抗和西罗莫司覆盖下移植同种异体胰岛的动物具有155、312、208、120、45天的移植物存活，建立了在移植中以非消耗方式阻断CD 40途径的潜力。未来的计划包括测试重组抗CD 40抗体，以更好地表征胰岛模型和移植中的CD 40阻断，并使用基于抗CD 40的生物方案来建立临床前数据，以转化为临床。