ANTI-THYMOGLOBUMLIN, CYCLOSPORIN AND RAD IN ISLET TRANSPLANT

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。这是一项I/II期研究，旨在评估顺序胰岛异体移植对1型糖尿病受体重建稳定血糖控制的安全性和有效性。总共有6名1型糖尿病患者将接受两次，也可能是三次来自不同供体胰腺的胰岛移植。胰岛异体移植的潜在候选者包括18岁及以上的1型糖尿病患者。首次移植的诱导免疫治疗将包括抗胸腺细胞球蛋白；Basiliximab将用于任何后续移植。每次胰岛移植均给予依那西普的移植周抗炎治疗。维持免疫抑制将使用环孢素和RAD。我们认为，那些代谢不稳定/不稳定、低血糖意识降低、血糖控制不良、持续进行性继发性并发症的患者，尽管与糖尿病护理团队密切合作，但仍有可能具有良好的获益/风险比。不良事件，无论其假定与异体胰岛移植和/或方案规定的治疗产品（伴随治疗）的关系如何，将在最终胰岛移植后的第一年监测和记录。在第一次、第二次或第三次同种异体胰岛移植后的第一年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前6周内不能实现胰岛素独立性，则需要进行第二次或第三次移植。将评估在最终胰岛移植一年后，单次和顺序供体同种异体胰岛移植受者完全（胰岛素依赖性，HbA1c <= 7%）和部分（胰岛素依赖性，基础或精氨酸刺激的c肽水平大于或等于0.5 ng/mL, HbA1c <= 7%）胰岛移植功能的比例。胰岛移植对生活质量的影响也将被评估。胰腺切除术前后胰岛素抵抗、移植细胞组成、移植β细胞数量等因素对移植后胰岛素独立性的预测价值；并评估离体胰岛的生存能力和胰岛素分泌反应。将要求GCRC提供实施该临床研究方案所需的结构。我们将同时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2天（第2天）入院，开始本方案所需的免疫治疗。他们将继续作为结直肠癌的住院患者，直到移植后第2天，以进行胰岛移植后的恢复、监测和继续免疫治疗。患者将作为门诊患者返回CRC进行15次移植后随访。需要CRC护理人员提供必要的仔细监测，以维持移植前后血糖在正常范围内。护理专业知识还将用于精确收集标本，并在胰岛移植手术后对患者进行仔细监测，以及随后的免疫治疗管理。

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.