ISLET-KIDNEY TRANSPLANTATION FOR TYPE I DIABETES

描述（改编自申请人的摘要）： 这项研究应用是建立临床协议，同时 1型糖尿病受者的胰岛-肾（IK）移植， 提供长期的营养和胰岛素依赖性。基于先前的人类 胰岛移植和实验证据，这项临床试验的SIK 移植将采用经过验证的和最近出现的方法和药物 来实现这一目标。总的来说，10%或更少的胰岛移植受者 在任何持续时间内实现胰岛素依赖性。最佳报道 单中心的结果是12名患者中有4名（25%）达到 胰岛-肾移植后的胰岛素依赖性。具体目标是 克服阻碍胰岛移植取得更好结果的三个障碍： 1)低移植胰岛质量; 2）高代谢需求和3）免疫移植 损失初步数据表明，改进的两步法用于胰岛 隔离，使用更好的保存溶液，是一种增加 移植胰岛质量。用普伐他汀治疗受体也可能 增加胰岛质量通过其能力，以防止非特异性 如动物模型中所证实的，对胰岛的炎性损伤。状态 通过胰岛素泵治疗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中毒。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。抗白细胞介素2 受体单克隆抗体有效地防止免疫移植物丢失， 糖尿病动物模型。这项试验将采用巴利昔单抗，一种嵌合的 抗IL 2受体抗体。胰周淋巴样细胞移植 也将用于防止移植物的自身免疫性破坏。结果 将测试本方案有效性的措施是精氨酸诱导的 胰岛素释放、正葡萄糖钳夹胰岛素敏感性指数与胰岛移植物 生存在改善的成功，西克移植可能最终 使胰岛移植在治疗 1型糖尿病

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.