ANTI-THYMOGLOBUMLIN, CYCLOSPORIN AND RAD IN ISLET TRANSPLANT

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。这是一项I/II期研究，旨在评估同种异体胰岛移植重建1型糖尿病患者血糖稳定控制的安全性和有效性。共有6名1型糖尿病患者将被登记接受来自不同供体胰腺的两次、可能三次胰岛移植。同种异体胰岛移植的潜在候选者将包括18岁及以上患有1型糖尿病的患者。第一次移植的诱导免疫治疗将包括抗胸腺细胞球蛋白；随后的任何移植将使用巴利昔单抗。每一次胰岛移植都将接受依那西普的围移植物抗炎治疗。维持免疫抑制将与环孢素和RAD一起使用。人们认为，那些代谢不稳定/不稳定、低血糖意识降低、血糖控制不佳以及进行性继发并发症的患者，尽管与他们的糖尿病护理团队密切合作，但仍持续进行着密集的努力，特别可能具有有利的收益/风险比。在最后一次胰岛移植后的第一年，将监测和记录不良事件，无论它们与同种异体胰岛移植和/或方案调节治疗产品(伴随治疗)的假定关系如何。在第一次、第二次或第三次同种异体胰岛移植后第一年内实现胰岛素独立的受试者比例将在一项前瞻性试验中进行评估。如果在胰岛移植后的头6周内不能实现胰岛素独立，将进行第二次移植，也可能是第三次移植。在最后一次胰岛移植后一年，对完全(胰岛素非依赖性，糖化血红蛋白=7%)和部分(胰岛素依赖，基础或精氨酸刺激的C-肽水平大于或等于0.5 ng/毫升，糖化血红蛋白=7%)胰岛移植物功能的单次和序贯供者胰岛移植受者的比例进行评估。还将评估胰岛移植对生活质量的影响。将评估胰岛素抵抗等因素对移植后胰岛素独立性的预测价值，这些因素包括胰腺切除前和切除后每隔一段时间的胰岛素抵抗、移植的细胞组成、移植的β细胞数量以及孤立胰岛的存活和胰岛素分泌反应。GCRC将被要求提供进行这项临床研究方案所需的结构。我们将使用住院和门诊病床来执行这项协议。患者将在胰岛细胞移植前两天(第2天)进入CRC，以开始该方案所需的免疫治疗。他们将继续作为住院的CRC患者，直到移植后第二天，用于胰岛移植后的恢复、监测和继续免疫治疗。患者将以门诊患者的身份返回CRC接受15次移植后的随访。需要CRC护理人员提供必要的仔细监测，以将移植前和移植后的血糖维持在正常范围内。还将依靠护理专业知识准确收集样本，并在胰岛移植手术后对患者进行仔细监测，并在实施免疫治疗后进行监测。

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. This is a Phase I/II study designed to assess the safety and efficacy of sequential islet allotransplantation for the reestablishment of stable glycemic control in trype 1 diabetic recipients. A total of 6 patients with type 1 diabetes will be enrolled to receive two, possibly three transplants of islets from different donor pancreases. Potential candidates for islet allotransplantation will include patients age 18 and older with trype 1 diabetes. Induction immunotherapy for the first transplant will consist of anti-thymocyte globulin; basiliximab will be used for any subsequent transplants. Peritransplant anti-inflammatory treatment with etanercept will be given for each islet transplant. Maintenance immunosuppression will be with cyclosporine and RAD. It is felt that those patients in whom metabolic lability/instability, reduced awareness of hypoglycemia, poor glycemic control, and progressive secondary complications persist despite continued and intensive efforts made in close cooperation with their diabetes care team are particularly likely to have a favorable benefit/risk ratio. Adverse events, irrespective of their presumed relationship to the transplantation of allogeneic islets and/or protocol-regulated treatment products (concomitant therapy), will be monitored and recorded throughout the first year after the final islet transplant. The proportion of subjects who achieve insulin independence in the first year after the first, second or third allogeneic islet transplant will be assessed in a prospective trial. In the event insulin independence is not achieved within the first 6 weeks after islet transplantation, a second and possibly a third transplant will be performed. The proportion of single and sequential donor islet allograft recipients with full (insulin independence and HbA1c <= 7% and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5 ng/mL and HbA1c <= 7%) islet graft function at one year after the final islet transplant will be assessed. The impact of islet transplantation on quality of life will also be assessed. The predictive value for posttransplant insulin independence of factors such as insulin resistance before and at intervals after pancreatectomy, cellular composition of the transplant, number of beta cells transplanted; and viability and insulin secretory response of isolated islets will be assessed. The GCRC will be asked to provide the structure necesary to conduct this clinical research protocol. We will use both the in and out patient beds in carrying out this protocol. Patients will be admitted to CRC two days prior to islet cell transplant (day-2) to begin the immunotherapy required for this protocol. They will remain as inpatients on CRC until day 2 post transplant for post islet transplant recovery, monitoring and continuation of immunotherapy. Patients will return to the CRC as outpatients for 15 post transplant follow up visits. The CRC nursing staff is needed to provide the careful monitoring necessary to maintain blood glucoses in the normoglycemic range pre and post transplant. Nursing expertise will also be relied on for precise collection of specimens and careful monitoring of patients after their islet transplant procedure and follwoing administration of immunotherapy.