ISLET TRANSPLANTATION IN TYPE 1 DIABETIC PATIENTS USING THE EDMONTON PROTOCOL

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 胰岛移植已被研究作为一种治疗1型糖尿病的选择患者血糖控制不足，尽管胰岛素治疗。然而，这种方法将导致长期不需要外源性胰岛素，并稳定糖尿病的继发性并发症的长期希望在实践中未能实现。在1990年以来移植的267例同种异体移植物中，只有12.4%的移植物在超过一周的时间内不依赖胰岛素，只有8.2%的移植物在超过一年的时间内不依赖胰岛素。在大多数这些precedures，免疫抑制方案包括抗体诱导与抗淋巴细胞球蛋白结合环孢素，硫唑嘌呤，糖皮质激素。 来自埃德蒙顿的Shapiro等人发表的对7名连续1型糖尿病受试者的观察结果表明，当无糖皮质激素的免疫抑制剂与足够胰岛质量的输注相结合时，胰岛移植可导致胰岛素非依赖性和良好的代谢控制。在该系列中，所有7名受试者在经皮经鞘门静脉胰岛移植后迅速达到持续的胰岛素依赖性。所有受体都需要来自两个供体胰腺的胰岛，一个需要来自两个供体的第三次移植以实现持续的胰岛素依赖性。几乎所有的供体胰腺在接受胰岛分离程序之前都曾因适合整个器官移植而被拒绝。移植后未再发生低血糖昏迷。 并发症很小，随访期间脂质浓度没有显著增加。 在对这份已发表报告的更新中，共有10名连续受试者在胰岛细胞移植和使用无糖皮质激素的免疫抑制方案（包括西罗莫司、低剂量他克莫司和抗白细胞介素-2受体的单克隆抗体（daclizumab））后保持胰岛素非依赖性。 该多中心可行性研究旨在确定在单中心获得的初步成功的再现性（Shapiro等人，埃德蒙顿的阿尔伯塔大学）。这将通过向参与研究的中心提供受试者选择、尸体供体资格、胰岛细胞处理、胰岛移植和移植后治疗方案的培训和标准化标准和程序来确定。根据本方案，最多10家临床试验机构共入组40例受试者。随访持续时间计划在第二次（或最终）移植后持续1年，研究应持续约2年。随访访视和评价时间表见附录1。

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. Islet transplantation has been investigated as a treatment for Type 1 diabetes mellitus in selected patients with inadequate glucose control despite insulin therapy. However, the perennial hope that such an approach would result in long-term freedom from the need for exogenous insulin, with stabilization of the secondary complications of diabetes, has failed to materialize in practice. Of the 267 allografts transplanted since 1990, only 12.4% have resulted in insulin independence for periods of more than one week, and only 8.2% have done os for periods of more than one year. In the majority of these precedures, the regimen of immunosuppression consisted of antibody induction with an antilymphocyte globulin combined with cyclosporine, azathioprine, and glucocorticoids. The published observationd by Shapiro, et al. from Edmonton, from a series of seven consecutive subjects with Type 1 diabetes, indicate that islet transplantation can result in insulin independence with excelent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass. In that series, all seven subjects quickly attained sustained insulin independence after percutaneous transhepatic portal vein transplantation of islets. All recipients required islets form two donor pancreases, and one required a 3rd transplant from two donors to achieve sustained insulin independence. Nearly all donor pancreata were previously rejected as suitable for whole organ transplant before being subject to the islet isolation procedures. There were no further episodes of hypoglycemic coma following transplant. Complications were minor, and there were no significant increases in lipid concentrations during follow-up. In an update to this published report, a total of 10 consecutive subjects have now remained insulin independent following islet cell transplant and use of a glucocorticoid-free immunosuppressive protocol that includes sirolimus, low-dose tacrolimus, and a monoclonal antibody against the interleukin-2 receptor (daclizumab). This multi-center feasiblity study is designed to determine the reproducibility of the preliminary success obtained at a single center (Shapiro, et al., University of Alberta in Edmonton). This will be determined by provideing the participated centers with training and standardized criteria and procedures for subject selection, cadaveric donor qualifications islet cell processing, islet transplantation, and post-transplant treatment regimens. A total of 40 subjects at up to 10 centers are to be enrolled under this protocol. The duration of follow-up is intended to last for 1 year after the second (or final) transplant and the study should last about 2 years. The schedule of follow-up visits and evaluations is shown in Appendix 1.