ISLET TRANSPLANTATION IN TYPE 1 DIABETIC PATIENTS USING THE EDMONTON PROTOCOL

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。 目的：确定Edmonton非类固醇免疫抑制方案在1型糖尿病患者胰岛移植临床多中心试验中的影响。主要目的是确认同种异体胰岛移植是研究耐受策略的合适模型，从而为未来的耐受干预和机制研究提供一个基线的患者队列。目前的研究将确定跨多个中心的临床胰岛移植的后勤基础设施。将为胰岛分离、移植、免疫抑制和详细后续行动的所有方面制定标准化方案，包括运送样本、与参考实验室的明确互动，包括耐受性分析小组和其他核心设施，以及开发用于统计分析的通用数据库(Emmes公司)。 基础/原理：临床胰岛移植受者将被证明是免疫耐受网络中耐受诱导方案早期评估的关键主要对象，因为与失去任何其他实体器官移植相比，移植物失败(返回胰岛素治疗)是无关紧要的。埃德蒙顿集团现有的初步数据显示，使用一种新的无类固醇免疫抑制疗法，在12名患者中100%成功地实现了持续的胰岛素独立，随访时间从1个月到18个月，与胰岛移植登记以前的报告相比有了显著的改善。其他中心在复制该方案和结果方面的成功程度将决定哪些中心可能参与未来的耐受策略。 与免疫耐受的意义和相关性：这项多中心研究将证明，在胰岛移植后，胰岛素的独立性可以始终如一地实现，在控制继发性糖尿病并发症方面，提供了一种比全胰腺移植侵入性小得多的方法。大的胰岛受体队列将为耐受性分析亚组提供重要的基线材料，可能允许在选定的病例中有效地取消免疫抑制。如果没有这项使用免疫抑制方法成功进行胰岛移植的重要基线试验，将很难确定作为这一倡议的第二阶段的未来耐受试验的有意义的结果。 方案概述：美国、加拿大和欧洲共有10个中心将对40名1型糖尿病患者进行单独的胰岛移植，采用Edmonton抗IL-2R受体抗体疗法诱导免疫抑制(Daclizumab)和西罗莫司和小剂量他克莫司非类固醇维持免疫抑制。胰岛将使用标准化的方案进行分离和提纯，并通过微创经皮经肝途径移植到门静脉。除了在单一参考实验室进行免疫组织化学细胞成分测定外，还将在静态葡萄糖孵育中完成具有胰岛素刺激反应的体外胰岛活性评估。胰岛将从两个供体器官中顺序移植，至少一周，但相隔不到3个月。胰岛素将在第二次移植后停用，代谢功能将由基础和精氨酸刺激的C肽水平决定。 GCRC的作用：GCRC将被要求提供进行这项临床研究试验所需的结构。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当天(第0天)进入GCRC，开始该方案所需的免疫治疗。他们将在移植后1天内继续在GCRC住院，以进行胰岛移植后的康复、监测和继续免疫治疗。病人将在第二天(第二天)出院。病人将以门诊病人的身份返回GCRC接受18次移植后的随访。GCRC的护理人员需要提供必要的仔细监测，以便在移植前后将血糖维持在正常血糖范围内。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和免疫治疗后对患者进行仔细监测。

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. Objectives: To determine the impact of the Edmonton protocol of steriod-free immunosuppression in a multi-center trial of clinical islet transplantation in type 1 diabetic patients. The primary objective will be to confirm that islet allotransplantion is an appropriate model for studying tolerance strategies, thus providing a baseline patient cohort for future interventions and mechanistic studies in tolerance. The current study will define the logistic infrastructure for clinical islet transplantation across multiple centers. Standardized protocols will be defined for all aspects of islet isolation, transplantation, immunosuppression, and detailed follow-up, including shipment of samples, defined interaction with reference laboratories including the tolerance assay subgroup and other core facilities, and development of a common database for statistical analysis (EMMES Corporation). Basis/Rationale: Clinical islet transplant recipients will prove to be key primary subjects for early evaluation of tolerance induction protocols in the Immune Tolerance Network, since graft failure (return to insulin therapy) is inconsequential compared to the loss of any other solid organ transplant. Existing preliminary data from the Edmonton group has demonstrated 100% success in achieving sustained insulin independence in 12 patients with a follow-up from 1 to 18 months using a novel steriod-free immunosuppressive regimen, representing dramatic improvement compared with previous reports from the Islet Transplant Registry. The degree of success by other centers in reproducing this protocol and results will determine which centers may participate in future tolerance strategies. Significance and Relevance to Immune Tolerance: This multicenter study will prove that insulin independence can be achieved consistently after islet transplantation, providing a much less invasive approach in control of secondary diabetic complications than whole pancreas transplantation. The large cohort of islet recipients will provide important baseline material for the tolerance assay subgroup, possibly allowing effective withdrawal of immunosuppression in selected cases. Without this important baseline trial of successful islet transplantation using an immunosuppressive approach, it will be very difficult to determine a meaningful outcome in future tolerance trials proposed as a second stage of this initiative. Protocol Summary: A total of 10 centers in the United States, Canada and Europe will perform solitary islet transplants in 40 type 1 diabetic patients using the Edmonton protocol of anti-IL-2R receptor antibody therapy induction immunuosuppression (daclizumab) with sirolimus and low-dose tacrolimus steroid-free maintenance immunosuppression. Islets will be isolated and purified using standardized protocols, and transplanted into the portal vein by a minimally invasive percutaneous transhepatic approach. In vitro islet viability assessment with insulin stimulation response in static glucose incubation will be completed in addition to immunohistochemical cell composition determination in a single reference laboratory. Islets will be transplanted sequentially from two donor organs at least one week, but less than 3 months apart. Insulin will be withdrawn after the second transplant, and metabolic function will be determined by basal and arginine-stimulated C-peptide levels. Role of GCRC: The GCRC will be asked to provide the structure necessary to conduct this clinical research trial. We will use both the in and outpatient beds in carrying out this protocol. Patients will be admitted to the GCRC the day of the islet cell transplant (day 0) to begin the immunotherapy required for this protocol. They will remain as inpatients on the GCRC for 1 day post transplant for post islet transplant recovery, monitoring and continuation of immunotherapy. Patients will be discharged on the second day (day 2). Patients will return to the GCRC as outpatients for 18 post transplant follow-up visits. The GCRC 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 upon for precise collection of specimens and careful monitoring of patients after their islet transplant procedure and following administration of immunotherapy.