STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

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。 我们最近发现，针对CD28/CD80/CD86和CD40/CD154共刺激通路，通过使用LEA29Y和Chi220，可以延长恒河猴异基因移植物的存活时间。基于这些结果，我们目前正在研究几种替代药物方案以及诱发糖尿病的替代方法。 为了扩大我们研究药理药物的能力，我们还在研究CTLA4Ig和3A8的作用，这两种药物同样分别抑制CD28/CD80/CD86和CD40/CD154通路。 虽然我们传统上使用保留十二指肠的胰腺切除术，但链脲佐菌素在其他模型中也用于制造糖尿病。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。在隔离三个月后，潜在的接受者进行了MHC分型，并接受了耳棒训练以监测血糖。在CTLA4Ig和3A8共刺激阻断方案的覆盖下，三只动物接受了链脲佐菌素诱导的糖尿病和随后的同种异体胰岛移植。该队列中的所有患者在移植后第一天空腹血糖正常化后立即具有同种异体移植的功能。我们目前正计划给更多的动物注射链脲佐菌素，并开始实验检查不同的解剖部位，如大网膜、肌肉和肾脏的包膜下间隙，以进行同种异体胰岛细胞移植。

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.