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。 目的：确定埃德蒙顿无类固醇免疫抑制方案在1型糖尿病患者临床胰岛移植多中心试验中的影响。 主要目的是确认胰岛同种异体移植是研究耐受性策略的合适模型，从而为将来的干预和耐受性机制研究提供基线患者队列。 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、免疫抑制和详细随访的所有方面制定标准化方案，包括样本运输、与参考实验室（包括耐受性试验亚组和其他核心设施）的明确互动，以及开发用于统计分析的通用数据库（EMMES Corporation）。 依据/理由：临床胰岛移植受者将被证明是免疫耐受网络中早期评价耐受诱导方案的关键主要受试者，因为与任何其他实体器官移植的损失相比，移植失败（恢复胰岛素治疗）无关紧要。 埃德蒙顿组现有的初步数据表明，12例患者使用新型无类固醇免疫抑制方案随访1至18个月，100%成功实现持续胰岛素依赖性，与胰岛移植登记处以前的报告相比，这是一个巨大的改善。 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性策略。 与免疫耐受的意义和相关性：这项多中心研究将证明胰岛移植后可以持续实现胰岛素非依赖性，为控制继发性糖尿病并发症提供了一种比全胰腺移植创伤小得多的方法。 大量的胰岛受体将为耐受性试验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。 如果没有这项重要的使用免疫抑制方法成功进行胰岛移植的基线试验，将很难确定作为该倡议第二阶段的未来耐受性试验的有意义的结果。 方案总结：美国、加拿大和欧洲共有10个中心将采用埃德蒙顿抗IL-2 R受体抗体治疗诱导免疫抑制（daclizumab）联合西罗莫司和低剂量他克莫司无类固醇维持免疫抑制方案，对40例1型糖尿病患者进行单独胰岛移植。 将使用标准化方案分离和纯化胰岛，并通过微创经皮经鞘入路移植到门静脉中。 除了在单个参考实验室中进行免疫组织化学细胞组成测定外，还将在静态葡萄糖孵育中使用胰岛素刺激反应完成体外胰岛活力评估。 胰岛将从两个供体器官连续移植，至少一周，但间隔不超过3个月。 胰岛素将在第二次移植后停用，代谢功能将通过基础和精氨酸刺激的C肽水平来确定。 GCRC的职责：将要求GCRC提供开展本临床研究试验所需的结构。 我们将使用住院和门诊床位执行本方案。 患者将在胰岛细胞移植当天（第0天）入住GCRC，以开始本方案所需的免疫治疗。 他们将在移植后1天继续作为GCRC的住院患者接受胰岛移植后恢复、监测和继续免疫治疗。 患者将在第二天（第2天）出院。 患者将作为门诊患者返回GCRC接受18次移植后随访访视。 需要GCRC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. 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.