ISLET-KIDNEY TRANSPLANTS FOR TREATMENT OF DIABETIC ESRD

用于治疗糖尿病 ESRD 的胰岛肾移植

• 批准号: 6665316
• 负责人: DAVID H SACHS
• 金额: $ 39.57万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-30 至 2004-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6665316
• 关键词: artificial immunosuppression; baboons; blood glucose; chronic renal failure; clinical research; diabetes mellitus therapy; diabetic nephropathy; glucose tolerance test; homologous transplantation; hyperglycemia; immunocytochemistry; kidney transplantation; miniature swine; nonhuman therapy evaluation; pancreatic islet transplantation; radioimmunoassay; streptozotocin; tissue /cell culture; transplantation immunology

DESCRIPTION (provided by applicant): Pancreatic islet transplantation is less efficient than whole organ pancreas transplantation in reversing the hyperglycemia of diabetes. One of the major reasons for this disparity is the loss of islets to ischemic injury during the time it takes for the islets to revascularize in the recipient. We have recently developed techniques for constructing composite "islet kidneys" (IK) by transplantation of autologous islets under the kidney capsule 2-3 months prior to transplantation of the composite organ into pancreatectomized miniature swine. Transplantation of IKs was found to restore euglycemia to pancreatectomized recipients immediately, and to maintain both renal and islet function long-term. Our preliminary data indicate further that a single living donor pancreas contains sufficient islets to support the insulin requirements of both the donor and recipient of such a prevascularized IK. The goal of this combined R21/R33 proposal is to perfect and optimize this approach in preclinical models (R21) and then to extend the procedure to the treatment of diabetic patients with end-stage renal disease. Specifically, in phase I (R21) we will: 1) Determine the optimal donor pancreatectomy requirements for clinical applicability; 2) Compare the efficacy of IK in maintaining euglycemia following tolerance induction vs. standard maintenance immunosuppression; 3) Establish an IK transplantation model in baboons and assess the ability of allogeneic IK transplantation to reverse hyperglycemia in diabetic baboons. In phase II (R33) we will: 1) Develop laparoscopic techniques for partial pancreatectomy, preparation of IK and IK removal for transplantation; and 2) Extend IK technology to the treatment of a major subset of patients with type 1 diabetes whose disease has progressed to end-stage renal failure. The research team assembled for this "bench-to-bedside" approach includes: 1) basic scientists in the Transplantation Biology Research Center, who have been responsible for the preliminary data on which the application is based, 2) clinicians at the Massachusetts General Hospital involved in transplantation and diabetes research, and 3) consultants with outstanding expertise related to the techniques to be developed. We anticipate that the use of pre-vascularized islets as part of a composite islet-kidney transplant may provide a new and effective treatment modality for patients with class I diabetes and end-stage renal disease.

描述（由申请人提供）： 在逆转糖尿病高血糖方面，胰岛移植的效率低于全器官胰腺移植。造成这种差异的主要原因之一是在受体体内胰岛血运重建期间，胰岛因缺血性损伤而损失。我们最近开发了构建复合“胰岛肾”（IK）的技术，在将复合器官移植到胰腺切除的小型猪中之前 2-3 个月，将自体胰岛移植到肾囊下。研究发现，IK 移植可以立即恢复胰腺切除受者的正常血糖，并长期维持肾脏和胰岛功能。我们的初步数据进一步表明，单个活体供体胰腺含有足够的胰岛来支持这种预血管化 IK 的供体和受体的胰岛素需求。 R21/R33 联合提案的目标是在临床前模型 (R21) 中完善和优化该方法，然后将该程序扩展到患有终末期肾病的糖尿病患者的治疗。具体来说，在第一阶段（R21）中，我们将： 1）确定临床适用性的最佳供体胰腺切除术要求； 2) 比较耐受诱导后 IK 维持血糖正常与标准维持免疫抑制的功效； 3）建立狒狒IK移植模型并评估同种异体IK移植逆转糖尿病狒狒高血糖的能力。在第二阶段（R33）中，我们将： 1）开发用于部分胰腺切除术、IK 准备和 IK 移植移植的腹腔镜技术； 2) 将 IK 技术扩展到治疗已发展至终末期肾衰竭的 1 型糖尿病患者的主要亚组。为这种“从实验室到临床”方法组建的研究团队包括：1）移植生物学研究中心的基础科学家，他们负责该应用程序所依据的初步数据，2）马萨诸塞州总医院的临床医生参与移植和糖尿病研究，以及 3) 具有与待开发技术相关的杰出专业知识的顾问。我们预计，使用预血管化胰岛作为胰岛-肾复合移植的一部分可能会为 I 类糖尿病和终末期肾病患者提供一种新的有效治疗方式。