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.

这个子项目是许多研究子项目中的一个 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。 我们最近发现，通过使用LEA 29 Y和Chi 220靶向CD 28/CD 80/CD 86和CD 40/CD 154共刺激通路，可以提高恒河猴同种异体移植物的存活率。 基于这些结果，我们目前正在研究几种替代药物方案以及糖尿病诱导的替代方法。 为了扩大我们研究药理学药物的能力，我们还研究了CTLA 4 Ig和3A 8的作用，它们同样分别抑制CD 28/CD 80/CD 86和CD 40/CD 154通路。 虽然我们传统上使用保留胰腺的胰腺切除术，但在其他模型中使用链脲佐菌素来产生糖尿病。 与胰腺切除术相比，链脲佐菌素有几个优点，包括避免了大手术及其相关风险，并保留了胰腺的外分泌功能。 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。 在隔离三个月后，对潜在的受体进行MHC分型，并进行耳贴训练以监测血糖。 三只动物在基于CTLA 4 Ig和3A 8共刺激阻断的方案的覆盖下经历了用链脲佐菌素的糖尿病诱导和随后的同种异体胰岛移植。 该队列中的所有受试者在移植后第1天具有即刻移植功能，空腹血糖正常化。 我们目前正计划将链脲佐菌素用于其他动物，并启动实验，检查不同的解剖部位，如网膜、肌肉和肾包膜下空间，以进行同种异体胰岛细胞移植。