ISLET TRANSPLANTATION FOR TYPE 1 DIABETES

1 型糖尿病的胰岛移植

• 批准号: 7604399
• 负责人: ALEXANDER C WISEMAN
• 金额: $ 0.94万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7604399
• 关键词: Adverse effects; Adverse event; Age-Years; Alberta province; Arginine; Awareness; C-Peptide; Caring; Clinical; Clinical Trials; Colorado; Computer Retrieval of Information on Scientific Projects Database; Cyclic GMP; Daclizumab; Dependence; Development; Diabetes Mellitus; Dose; Fc Receptor; Foundations; Funding; Glycosylated Hemoglobin; Grant; Guidelines; Health Sciences; Human; Hypoglycemia; Immune Tolerance; Immunosuppression; Institution; Insulin; Insulin-Dependent Diabetes Mellitus; Islet Cell; Islets of Langerhans; Islets of Langerhans Transplantation; Label; Laboratories; Metabolic; Methodology; Monitor; National Center for Research Resources; Outcome; Pancreas; Patients; Population; Preparation; Procedures; Protocols documentation; Reporting; Research; Research Personnel; Resources; Safety; Sirolimus; Source; Standards of Weights and Measures; Steroids; Tacrolimus; Therapeutic immunosuppression; Titrations; Transplantation; Treatment Protocols; United States National Institutes of Health; Universities; cohort; experience; glycemic control; graft function; islet; islet allograft; novel; pilot trial; success; transplantation typing; type I diabetic

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. The objective of this application is to utilize GCRC resources for use of freshly isolated human pancreatic islets for the treatment of type 1 diabetes. Islet allografts have been performed in nearly 400 patients with type1 diabetes since the early 1970's, but prior to the "Edmonton experience", only forty-one recipients of this cohort had achieved insulin independence following transplantation. Islet transplantation as a treatment for type1 diabetes took a dramatic step forward with successes reported at the University of Alberta in Edmonton. This group demonstrated consistent reversal of Type1 diabetes following sequential islet transplantation from two donor pancreases and subsequent immunosuppression with a novel, steroid-free regimen including interlukin-2 receptor antibody daclizumab, sirolimus, and low-dose tacrolimus. The rationale behind the Edmonton approach had been to maximize the potential for insulin by titration of an adequate islet transplant mass so that the potential side effects of immunosupression are outweighed by the benefits of insulin independence and tight glycemic control. The success of the Edmonton Protocol has provoked the creation of an NIH-funded clinical trial (the Immune Tolerance Network Islet Transplant Trial enlisting 10 centers worldwide to emulate the methodology of the U of Alberta),the development of Islet Transplant Centers funded by the Juvenile Diabetes Research Foundation, and the development of "Islet Cell Resource Centers" (ICRs) funded by the NIH (NCRR) to optimize the use of each pancreas for potential transplant. Our center, the University of Colorado Health Sciences Center, was one of 10 centers selected for participation as an Islet Cell Resource Center. At present, our laboratory has gained NIH approval for islet isolation under cGMP guidelines and has performed 41 pancreatic islet isolation procedures over 18 months. Our facility is now prepared to move toward clinical use of our human islet preparations. We plan to emulate the Edmonton protocol as a standard from which to assess function and outcomes of islet transplantation prior to transitioning to novel treatment protocols and patient populations. The objective of this study is to assess the safety and efficacy of islet allotransplantation for the re-establishment of stable glycemic control in patients with type 1 diabetes in an open-label, single-center pilot trial. Potential candidates for islet allotransplantation will include patients greater than or equal to 18 years of age with type 1 diabetes in whom metabolic liability/instability, reduced awareness of hypoglycemia, progressive secondary complications despite intensive management, in cooperation with their diabetes care team. Adverse events will be monitored and recorded throughout the first two years post-transplant. The proportion of type 1 diabetic islet allograft recipients with full (insulin independence and HbA1c7%) and partial (insulin dependence, basal or arginine-stimulated C-peptide levels of greater or equal to 0.5ng/mL and glycated hemoglobin less than or equal to 7%) islet graft function at one year post transplant and beyond will be assessed.

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。子项目和 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。 本申请的目的是利用GCRC资源使用新鲜分离的人胰岛治疗1型糖尿病。自20世纪70年代早期以来，已经在近400例1型糖尿病患者中进行了胰岛同种异体移植，但在“埃德蒙顿经验”之前，该队列中只有41例接受者在移植后实现了胰岛素依赖性。 胰岛移植作为1型糖尿病的治疗方法向前迈出了戏剧性的一步，埃德蒙顿的阿尔伯塔大学报道了成功。 这一组显示了从两个供体胰腺连续胰岛移植和随后的免疫抑制与一种新的，无类固醇的方案，包括白细胞介素-2受体抗体daclizumab，西罗莫司和低剂量他克莫司的1型糖尿病的一致逆转。埃德蒙顿方法背后的基本原理是通过滴定足够的胰岛移植物质量来最大化胰岛素的潜力，使得免疫抑制的潜在副作用被胰岛素非依赖性和严格血糖控制的益处所超过。埃德蒙顿方案的成功激发了NIH资助的临床试验的创建（免疫耐受网络胰岛移植试验在全世界招募了10个中心来模仿阿尔伯塔大学的方法），由青少年糖尿病研究基金会资助的胰岛移植中心的发展，以及由美国国立卫生研究院（NCRR）资助的“胰岛细胞资源中心”（ICR）的发展，以优化每个胰腺的潜在移植使用。 我们的中心，科罗拉多大学健康科学中心，是10个被选为胰岛细胞资源中心的中心之一。 目前，我们的实验室已获得NIH批准，可根据cGMP指南进行胰岛分离，并在18个月内进行了41次胰岛分离程序。 我们的设施现在准备走向临床使用我们的人胰岛制剂。 我们计划模仿埃德蒙顿方案作为标准，在过渡到新的治疗方案和患者人群之前评估胰岛移植的功能和结果。本研究的目的是在一项开放标签、单中心的初步试验中评估同种异体胰岛移植对1型糖尿病患者血糖控制恢复稳定的安全性和有效性。胰岛同种异体移植的潜在候选者将包括年龄大于或等于18岁的1型糖尿病患者，这些患者在与糖尿病护理团队合作的情况下存在代谢易患性/不稳定性、对低血糖的认识降低、尽管进行了强化管理但仍发生进展性继发性并发症。将在移植后的头两年监测和记录不良事件。将评估移植后1年及以后具有完全（胰岛素非依赖性和HbA1c7%）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，糖化血红蛋白小于或等于7%）胰岛移植物功能的1型糖尿病胰岛移植物接受者的比例。