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.

该副本是利用众多研究子项目之一 由NIH/NCRR资助的中心赠款提供的资源。子弹和 调查员（PI）可能已经从其他NIH来源获得了主要资金， 因此可以在其他清晰的条目中代表。列出的机构是 对于中心，这不一定是调查员的机构。 在本报告期间，由于渴望更佳的生物免疫抑制方案，因此没有进行进一步的胰岛质量或解剖部位实验。为了寻找一种更临床相关的毒性较小的毒性，灵长类动物被移植了抗LFA-1单克隆抗体的疗法的同种异体胰岛，结果非常有希望。在我们的临床前胰岛移植模型中，抗LFA-1已被证明是非常有效的免疫抑制剂，这是其在临床试验中使用的理由。尽管最近使用了纯生物学方案，抗LFA-1 MAB和BELATACEPT，但更有希望的是，导致367、223、373、73和269天的糖尿病和胰岛存活立即逆转。这种生物学方案有望成为一种临床相关，可耐受性的方案，并有可能转化为诊所。 此外，我们研究了3A8的使用，3A8是一种靶向CD40的无抑制小鼠单克隆抗体。动物在3A8，贝拉昔单抗和西罗莫司的覆盖下移植了同种异体胰岛，其移植物存活率为155、312、208、120、45天，在移植中以不足的方式阻止CD40途径的潜力。未来的计划包括重组抗CD40抗体的测试，以更好地表征我们的胰岛模型和移植中CD40-Blockade，以及使用基于抗CD40的生物学方案来建立临床前数据，以建立临床前数据，以转化为诊所。