ISLET-KIDNEY TRANSPLANTATION FOR TYPE I DIABETES

I 型糖尿病的胰岛肾移植

• 批准号: 6929093
• 负责人: CRAIG V SMITH
• 金额: $ 96.96万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-15 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6929093
• 关键词: antiinflammatory agents; antireceptor antibody; artificial endocrine pancreas; bioenergetics; clinical research; cytokine receptors; diabetes mellitus therapy; human subject; human therapy evaluation; insulin dependent diabetes mellitus; interleukin 2; kidney transplantation; lymphatic tissue transplantation; pancreatic islet transplantation; transplant rejection; troglitazone

DESCRIPTION (Adapted from the Applicant's Abstract): The overall objective of this research application is to establish clinical protocols for simultaneous islet-kidney (SIK) transplantation in type 1 diabetic recipients that will provide long-term euglycemia and insulin-independence. Based on prior human islet transplants and experimental evidence, this clinical trial of SIK transplantation will apply proven and recently emerging methods and medications to achieve this goal. Overall, 10% or less of islet transplant recipients have achieved insulin-independence for any sustained period. The best reported results from a single center are four of 12 patients (25%) achieving insulin-independence following islet-kidney transplants. The specific aims are to overcome three obstacles that prevent better results in islet transplants: 1) low engrafted islet mass; 2) high metabolic demand and 3) immunologic graft loss. Preliminary data suggest that an improved two-step method for islet isolation, using a better preservation solution, is a means to increase the engrafted islet mass. Treatment of recipients with pravastatin may also increase the islet mass through its ability to prevent non-specific inflammatory damage to islets, as demonstrated in animal models. State of the art glycemic control with insulin pump therapy and subcutaneously implanted glucose sensors will help to prevent glucotoxicity. The investigators will use recipient treatment with thiazolidinedione class medications to lower the metabolic demand by increasing peripheral sensitivity to insulin. Anti-IL2 receptor monoclonal antibodies effectively prevent immunologic graft loss in animal models for diabetes. This trail will employ basiliximab, a chimeric anti-IL2 receptor antibody. Transplantation of peripancreatic lymphoid cells will also be used to prevent autoimmune destruction of the grafts. Outcome measures that will test the effectiveness of this protocol are arginine induced insulin release, euglycemic clamp insulin sensitivity indices and islet graft survival. Improvements in the success of SIK transplantation may eventually lead to more wide spread application of islet transplantation to the cure of type 1 diabetes.

描述（改编自申请人的摘要）：总体目标 这项研究应用是建立同时进行的临床方案 1 型糖尿病患者的胰岛肾 (SIK) 移植 提供长期的血糖正常和胰岛素非依赖性。基于先验人类 胰岛移植和实验证据，SIK 的这项临床试验 移植将应用经过验证的和最近出现的方法和药物 为了实现这个目标。总体而言，10% 或更少的胰岛移植受者 在任何持续时期内实现胰岛素独立。最好的报道 单个中心的结果是 12 名患者中有 4 名 (25%) 达到了 胰岛肾移植后的胰岛素依赖性。具体目标是 克服阻碍胰岛移植获得更好结果的三个障碍： 1) 移植胰岛质量低； 2）高代谢需求和3）免疫移植 损失。初步数据表明，改进的胰岛两步法 隔离，使用更好的保存溶液，是增加 移植的胰岛块。用普伐他汀治疗受者也可能 通过其防止非特异性的能力来增加胰岛质量 正如动物模型所证明的，对胰岛的炎症损伤。的状态 通过胰岛素泵疗法和皮下植入进行血糖控制 葡萄糖传感器将有助于防止葡萄糖毒性。调查人员将使用 接受噻唑烷二酮类药物治疗以降低 通过增加外周对胰岛素的敏感性来满足代谢需求。抗IL2 受体单克隆抗体可有效预防免疫移植物丢失 糖尿病动物模型。该试验将使用巴利昔单抗，一种嵌合体 抗IL2受体抗体。胰周淋巴细胞移植 还将用于防止移植物的自身免疫性破坏。结果 测试该方案有效性的措施是精氨酸诱导的 胰岛素释放、正常血糖钳夹胰岛素敏感性指数和胰岛移植 生存。 SIK 移植的成功率最终可能会提高 使得胰岛移植在治疗糖尿病方面得到更广泛的应用 1 型糖尿病。