STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

大规模胰岛置换策略

• 批准号: 7958210
• 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: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7958210
• 关键词: Allogenic; Allografting; Anatomic Sites; Animals; Ascaridil; Blood Glucose; Clinical Trials; Computer Retrieval of Information on Scientific Projects Database; Diabetes Mellitus; Fasting; Funding; Grant; Immunosuppressive Agents; Institution; Islets of Langerhans Transplantation; LEA29Y; Macaca mulatta; Modeling; Muscle; Pathway interactions; Primates; Reporting; Research; Research Personnel; Resources; Source; Streptozocin; Transplantation; Treatment Protocols; United States National Institutes of Health; anti-LFA-1 monoclonal antibody; base; clinically relevant; cohort; islet; pre-clinical; research study; success

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. 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 (Adams et al., J Immunol 2005). 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, proving 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, 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 60 days. This biologic regimen promises to be a clinically relevant, tolerable regimen ideal for use in the optimization of islet mass and anatomic site for islet transplantation.

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 我们已经证明，通过使用LEA29Y和Chi220靶向CD28/CD80/CD86和CD40/CD154共刺激通路，可以延长恒河猴的同种异体移植物存活时间(Adams等人，《免疫杂志》2005)。基于这些结果，我们研究了同样抑制CD28/CD80/CD86和CD40/CD154通路的CTLA4Ig和3A8的作用。在这个队列中的所有受者都有立即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，证明基于共刺激阻断的方案在胰岛移植中继续取得成功。在使用链脲佐菌素过渡到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位置。其中一只动物将15000IE/kg的同种异体胰岛移植到斜方肌和背阔肌中，取得了一定的成功。 在本报告期间，由于对更理想的生物免疫抑制方案的渴望，没有进行进一步的胰岛肿块或解剖部位实验。为了寻找一种更具临床意义、毒性更低的治疗方案，灵长类动物在抗LFA-1单抗治疗的覆盖下进行了同种异体胰岛移植，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，这为其在临床试验中的使用奠定了基础。 然而，更有希望的是最近使用了一种纯粹的生物方案，抗LFA-1单抗和贝拉塔塞普单独使用，导致糖尿病立即逆转，胰岛存活60天。这种生物方案有望成为一种临床相关、耐受性好的方案，用于优化胰岛质量和胰岛移植的解剖部位。