Islet Transplant - Costimulatory Blockade with LEA29Y

胰岛移植 - LEA29Y 共刺激阻断

• 批准号: 6953744
• 负责人: ANDREW M SHAPIRO
• 金额: $ 266万
• 依托单位: UNIVERSITY OF ALBERTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-30 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6953744
• 关键词: CD28 molecule; autoimmunity; chemotherapy; clinical research; clinical trials; cooperative study; diabetes mellitus; human subject; human therapy evaluation; immunosuppressive; pancreatic islet transplantation; patient oriented research; sirolimus; transplantation immunology

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 diabetbgenic 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 (approximately 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.

描述（由申请人提供）：目前来自世界各地胰岛移植中心的数据表明，在使用基于西罗莫司、无类固醇、低剂量他克莫司治疗的情况下，通常需要不止一个供体胰腺移植才能实现胰岛素独立性。此外，这些患者还会出现并发症，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。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basiliximab诱导，维持治疗包括LEA29Y （BMS224818）和低剂量西罗莫司，从而避免使用两种有效但会引起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，该计划旨在定义一个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)通过单一供体胰岛移植显著提高胰岛素独立性的发生率，3)在移植完成后1年维持或提高总体胰岛素独立性的优秀率（约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，在预防排斥或复发性自身免疫方面具有相当的疗效，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。除了评估临床结果外，还将进行机制研究：(1)深入了解与异体胰岛移植存活相关的免疫学机制；(2)确定胰岛移植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。