ANTI-THYMOGLOBUMLIN, CYCLOSPORIN AND RAD IN ISLET 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。子项目及 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。 这是一项I/II期研究，旨在评估序贯胰岛同种异体移植在1型糖尿病受者中重建稳定血糖控制的安全性和有效性。总共6名1型糖尿病患者将被招募接受来自不同供体胰腺的两次，可能三次胰岛移植。胰岛同种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;巴利昔单抗将用于任何后续移植。每次胰岛移植时，将给予依那西普的移植物周围抗炎治疗。维持免疫抑制将与环孢素和RAD。认为代谢不稳定/不稳定、低血糖意识降低、血糖控制不佳和进行性继发性并发症持续存在的患者，尽管与糖尿病护理团队密切合作，持续进行密集努力，但特别可能具有有利的获益/风险比。将在末次胰岛移植后的第一年内监测和记录不良事件，无论其与同种异体胰岛移植和/或方案规定的治疗产品（伴随治疗）的假定关系如何。将在一项前瞻性试验中评估在第一次、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非依赖性的受试者比例。如果在胰岛移植后的前6周内未实现胰岛素依赖性，则将进行第二次和可能的第三次移植。将评估在最后一次胰岛移植后1年时具有完全（胰岛素非依赖性和HbA 1c <= 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和HbA 1c <= 7%）胰岛移植物功能的单次和连续供体胰岛同种异体移植物接受者的比例。还将评估胰岛移植对生活质量的影响。将评估以下因素对移植后胰岛素不依赖性的预测值：胰腺切除术前和术后间隔时的胰岛素抵抗、移植物的细胞组成、移植的β细胞数量;以及分离胰岛的活力和胰岛素分泌反应。将要求GCRC提供执行本临床研究方案的结构表。我们将在执行本方案时使用住院和门诊病床。患者将在胰岛细胞移植前两天（第2天）入住CRC，以开始本方案所需的免疫治疗。他们将继续作为CRC住院患者，直至移植后第2天，以进行胰岛移植后恢复、监测和继续免疫治疗。患者将作为门诊患者返回CRC接受15次移植后随访访视。CRC护理人员需要提供必要的仔细监测，以维持移植前后血糖在正常血糖范围内。护理专业知识也将依赖于精确收集标本和仔细监测病人后，他们的胰岛移植程序和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.