STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

大规模胰岛置换策略

• 批准号: 7562676
• 负责人: THOMAS C PEARSON
• 金额: $ 3.95万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-05-01 至 2008-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562676
• 关键词: Allografting; Anatomic Sites; Animals; Biological Preservation; Blood Glucose; Cell Transplants; Computer Retrieval of Information on Scientific Projects Database; Diabetes Mellitus; Ear; Fasting; Funding; Grant; Institution; Kidney; LEA29Y; Macaca; Macaca mulatta; Methods; Modeling; Muscle; Omentum; Operative Surgical Procedures; Pancreas; Pancreatectomy; Pathway interactions; Pharmaceutical Preparations; Quarantine; Research; Research Personnel; Resources; Risk; Source; Streptozocin; Training; Transplantation; Treatment Protocols; United States National Institutes of Health; base; cohort; day; germ free condition; glucose monitor; islet; 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. We have recently shown that targeting the CD28/CD80/CD86 and CD40/CD154 costimulatory pathways, by using LEA29Y and Chi220, prolongs allograft survival in rhesus macaques. Based on these results, we are currently investigating several alternative drug regimens as well as alternative methods of diabetes induction. In an effort to expand our ability to investigate pharmacologic agents, we are also examining the effects of CTLA4Ig and 3A8, which likewise inhibit the CD28/CD80/CD86 and CD40/CD154 pathways, respectively. While we traditionally use the duodenal-sparing pancreatectomy, streptozotocin is used in other models to produce diabetes. Streptozotocin has several advantages over pancreatectomy including the avoidence of a major operation with its associated risks and preservation of the exocrine function of the pancreas. In August of 2006, 11 specific pathogen-free macaques were obtained to be used in part for this project. After three months in quarantine, potential recipients were MHC typed and underwent ear stick training for blood glucose monitoring. Three animals have undergone diabetes induction with streptozotocin and subsequent alloislet transplant under cover of a CTLA4Ig and 3A8 cotimulation blockade-based regimen. All recipeints in this cohort have had immediate allograft function with normalization of fasting blood sugars by day 1 post-transplant. We are currently planning to administer streptozotocin to additional animals and initiate experiments examining different anatomic sites such as the omentum, the muscle, and the subcapsular space of the kidney for alloislet cell transplant.

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。子项目和 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。 我们最近表明，通过使用 LEA29Y 和 Chi220 靶向 CD28/CD80/CD86 和 CD40/CD154 共刺激途径，可以延长恒河猴同种异体移植物的存活时间。 基于这些结果，我们目前正在研究几种替代药物疗法以及诱导糖尿病的替代方法。 为了扩大我们研究药物的能力，我们还在研究 CTLA4Ig 和 3A8 的作用，它们同样分别抑制 CD28/CD80/CD86 和 CD40/CD154 途径。 虽然我们传统上使用保留十二指肠的胰腺切除术，但链脲佐菌素也用于其他模型来产生糖尿病。 链脲佐菌素比胰腺切除术有几个优点，包括避免大手术及其相关风险以及保留胰腺的外分泌功能。 2006年8月，获得了11只无特定病原体的猕猴，部分用于该项目。 隔离三个月后，潜在的接受者进行了 MHC 分型，并接受了耳棒血糖监测训练。 三只动物在基于 CTLA4Ig 和 3A8 共刺激阻断的方案的掩护下接受了链脲佐菌素诱导糖尿病和随后的同种异体移植。 该队列中的所有配方均具有立即同种异体移植功能，移植后第 1 天空腹血糖正常化。 我们目前正计划对其他动物施用链脲佐菌素，并启动实验检查不同的解剖部位，例如大网膜、肌肉和肾脏的囊下空间，以进行同种胰岛细胞移植。