ISLET-KIDNEY TRANSPLANTATION FOR TYPE I DIABETES

描述(改编自申请人的摘要)：总体目标 这项研究的应用是为了建立同步的临床方案 胰岛-肾(SIK)移植治疗1型糖尿病受者 提供长期的正常血糖和胰岛素非依赖性。基于之前的人类 胰岛移植及实验证据--SIK的临床试验 移植将应用经过验证的和新近出现的方法和药物 来实现这一目标。总体而言，10%或更少的胰岛移植接受者 在任何持续的时期内实现胰岛素独立。最好的报道 来自一个中心的结果是12名患者中有4名(25%)实现了 胰岛肾移植后的胰岛素非依赖性。具体目标是 要克服阻碍胰岛移植取得更好效果的三个障碍： 1)低移植胰岛质量；2)高代谢需求；3)免疫移植物 损失。初步数据表明，一种改进的两步法用于胰岛 隔离，使用更好的保存液，是一种增加 植入胰岛团块。普伐他汀对受体的治疗也可能 通过其防止非特异性的能力来增加胰岛质量 如动物模型所示，胰岛的炎性损伤。国家的现状 胰岛素泵治疗的ART血糖控制和皮下植入 葡萄糖传感器将有助于预防糖毒性。调查人员将使用 用噻唑烷二酮类药物治疗受者以降低 通过增加外周对胰岛素的敏感性来满足代谢需求。抗IL-2抗体 受体单抗有效预防免疫性移植物丢失 糖尿病的动物模型。这条路将使用basiliximab，一种嵌合体 抗IL2受体抗体。胰周淋巴样细胞移植 也将被用来防止移植物的自身免疫破坏。结果 将测试该协议有效性的措施是精氨酸诱导 胰岛素释放、正糖钳夹胰岛素敏感指数与胰岛移植物 生死存亡。SIK移植成功率的提高最终可能会 使胰岛移植在治疗糖尿病中得到更广泛的应用 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.