Clinical Refinement of islet transplantation

描述（由申请人提供）： 来自世界范围内进行胰岛移植的中心的当前数据表明，在存在基于西罗莫司、无类固醇、低剂量他克莫司治疗的情况下，通常需要一个以上的供体胰腺移植物来实现胰岛素依赖性。此外，在这些患者中还出现了包括加速肾毒性（来自他克莫司）、口腔溃疡、血脂异常和高血压在内的并发症。本研究旨在通过使用一种新的免疫抑制方案来解决这些问题，该方案包括巴利昔单抗诱导，维持治疗包括LEA 29 Y（BMS 224818）和低剂量西罗莫司，从而避免使用两种有效但致糖尿病的免疫抑制剂-类固醇和钙调磷酸酶抑制剂。本提案中描述的临床试验代表了总体开发计划的第一步，该计划旨在定义实现三个目标的方案; 1）减少或消除与埃德蒙顿方案相关的非免疫毒性，2）促进用来自单个供体的胰岛移植物实现胰岛素非依赖性的显著更高的比率，（3）维持或提高完成移植后1年胰岛素依赖性的总体优良率（~80%）。我们的中心假设是，使用免疫选择性CD 28阻断剂LEA 29 Y作为主要药物，在预防排斥反应或复发性自身免疫方面具有相当的疗效，同时允许从我们的免疫抑制方案中消除他克莫司和西罗莫司（如有必要）。除了评估临床结局外，还将进行机制研究，以：（1）深入了解与胰岛移植物存活相关的免疫学机制，（2）确定胰岛移植物的生理能力和功能活力。这些研究将有助于改善对这些患者的护理。 相关性（由申请人提供）：本提案是总体开发计划的一部分，旨在定义实现三个目标的协议：1）减少或消除与埃德蒙顿方案相关的非免疫毒性，2）促进用来自单个供体的胰岛移植物实现胰岛素非依赖性的显著更高的比率，（3）维持或提高完成移植后1年的胰岛素依赖率。

DESCRIPTION (provided by applicant): Current data from centers performing islet transplantation worldwide indicates that in the presence of sirolimus-based, steroid-free, low-dose tacrolimus therapy, usually more than one donor pancreas graft is required to attain insulin independence. Furthermore, complications including accelerated nephrotoxicity (from tacrolimus), mouth ulceration, dyslipidemia and hypertension have been encountered in these patients. This study aims to address these issues with through the use of a novel immunosuppressive regimen comprised of basiliximab induction, with maintenance therapy including LEA29Y (BMS224818) and low dose sirolimus thus avoiding the use of two potent but diabetogenic immunosuppressive agents- steroids and calcineurin inhibitors. The clinical trial described in this proposal represents the first step of an overall development plan designed to define a protocol that achieves three goals; 1) to reduce or eliminate non- immune toxicities associated with the Edmonton Protocol, 2) to promote significantly higher rates of achieving insulin independence with islet transplants from single donors, and 3) to maintain or improve the overall excellent rates of insulin-independence (~80%) at I year after the completion transplant. Our central hypothesis is that the use of the immunoselective CD28 blocker, LEA29Y as the primary agent will allow comparable efficacy in preventing rejection or recurrent autoimmunity while permitting the elimination of tacrolimus and if necessary sirolimus from our immunosuppressive regimen. In addition to the assessment of clinical outcome, mechanistic studies will be performed to: (1) provide insight into the immunological mechanisms associated with islet allograft survival and (2) determine the physiological capacity and functional viability of islet grafts. The studies will facilitate the development of improved care for these patients. RELEVANCE (provided by applicant): This proposal is part of an overall development plan to define a protocol that achieves three goals: 1) to reduce or eliminate non-immune toxicities associated with the Edmonton Protocol, 2) to promote significantly higher rates of achieving insulin independence with islet transplants from single donors, and 3) to maintain or improve the rates of insulin-independence at I year after the completion transplant.