Islet Transplant - Costimulatory Blockade with LEA29Y

胰岛移植 - LEA29Y 共刺激阻断

• 批准号: 6887122
• 负责人: ANDREW M SHAPIRO
• 金额: $ 290万
• 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/6887122
• 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）：全球进行胰岛移植中心的当前数据表明，在存在基于西罗莫司的，无类固醇，低剂量的他克莫司疗法的情况下，通常需要多个供体胰腺移植物才能获得胰岛素独立性。此外，这些患者遇到了包括加速性肾毒性（来自他克莫司），口腔溃疡，血脂异常和高血压的并发症。这项研究的目的是通过使用一种由basiliximab诱导组成的新型免疫抑制疗法来解决这些问题，其中包括LEA29Y（BMS224818）和低剂量的西罗洛姆斯（Sirolimus）的维护疗法，因此避免了使用两个有效但糖尿病性免疫抑制剂的固醇和钙化剂的使用。本提案中描述的临床试验是整体开发计划的第一步通过从单个供体的胰岛移植和3）实现胰岛素独立性，以维持或提高完成移植后I年的胰岛素独立性（约80％）的总体优异率。我们的中心假设是，使用免疫选择性CD28阻滞剂LEA29Y作为主要药物将允许在防止拒绝或复发自身免疫性方面具有可比的功效，同时允许消除他克莫司，并在必要时从我们的免疫抑制方案中获得西洛洛里姆斯。除了评估临床结果外，还将进行机械研究，以：（1）洞悉与同种异体移植生存相关的免疫机制，（2）确定胰岛移植物的生理能力和功能可行性。这些研究将促进这些患者改善护理的发展。