Clinical Refinement of islet transplantation

描述(由申请人提供)： 来自世界各地进行胰岛移植的中心的最新数据表明，在使用基于西罗莫司的、非类固醇的、低剂量的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才能实现胰岛素独立。此外，这些患者还出现了加速肾毒性(由他克莫司引起)、口腔溃疡、血脂异常和高血压等并发症。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LEA29Y(BMS224818)和小剂量西罗莫司，从而避免使用两种有效的糖尿病免疫抑制药-类固醇和钙调神经磷酸酶抑制剂。这项建议中描述的临床试验是总体开发计划的第一步，该计划旨在确定一项协议，以实现三个目标：1)减少或消除与埃德蒙顿协议有关的非免疫毒性，2)促进通过单一捐赠者的胰岛移植获得更高的胰岛素独立率，以及3)在完成移植后一年维持或提高胰岛素独立率的总体优良率(~80%)。我们的中心假设是，使用免疫选择性CD28阻滞剂LEA29Y作为主要药物，将在预防排斥或复发自身免疫方面具有类似的疗效，同时允许从免疫抑制方案中消除他克莫司和必要时的西罗莫司。除了临床结果的评估外，还将进行以下机制研究：(1)深入了解与同种异体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性。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)：这项建议是一个总体开发计划的一部分，以确定一项实现三个目标的协议：1)减少或消除与埃德蒙顿协议有关的非免疫毒性，2)促进通过单一捐赠者的胰岛移植实现更高的胰岛素独立率，以及3)在完成移植后一年维持或提高胰岛素独立率。

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.