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; 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.

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。 我们已经表明，针对CD28/CD80/CD86和CD40/CD154 costimulation途径，使用LEA29Y和CHI220延长了恒河猕猴中同种异体移植的存活（Adams等人，J Immunol 2005）。基于这些结果，我们研究了CTLA4IG和3A8的影响，它们同样抑制了CD28/CD80/CD86和CD40/CD154途径。该队列中的所有接受者都具有立即的同种异体移植功能，其禁食血糖正常化和长期同种异体移植生存率，证明基于共刺激的基于封锁的方案在胰岛移植方面继续取得成功。在使用链霉菌素过渡到新的糖尿病诱导模型后，实验开始确定最佳的胰岛质量和解剖部位的胰岛移植。一只动物被肌肉内的15,000ie/kg同种异体胰岛移植到斜方肌和latissimus dorsi肌肉中，并以中等的成功。 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，但更有前途的是，立即逆转了糖尿病和胰岛存活60天。这种生物学方案有望成为一种临床相关的，可耐受性的方案，非常适合优化胰岛质量和解剖部位进行胰岛移植。