Autoimmunity Center of Excellence

自身免疫卓越中心

• 批准号: 8070549
• 负责人: David Wofsy
• 金额: $ 52.81万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8070549
• 关键词: Autoimmunity; Center; Excellence

DESCRIPTION (provided by applicant): The central theme of this application is to clarify the role of regulatory T cells (Treg) in autoimmune diseases and explore their potential as therapeutic agents. Toward this end, we propose a tightly focused, fully integrated set of laboratory and clinical studies. Specifically, our proposal includes: Clinical Center (David Wofsy, PI): Investigators involved in this application have extensive experience in the conduct of clinical trials in diverse autoimmune diseases. Two concept proposals are presented. Protocol 1 is a phase Ib/lla trial of anti-CD20 plus cyclophosphamide (IVC) as induction therapy in patients with active lupus nephritis. It will test the hypothesis that the use of IVC in conjunction with anti-CD20 will promote emergence of Tregs and thereby provide sustained clinical benefit. Protocol 2 is a phase II trial of imatinib (Gleevec(r)) in patients with new-onset type I diabetes mellitus. This trial is based on extensive pre-clinical work in our own laboratories. It will test the hypothesis that imatinib eliminates activated autoreactive T cells and thereby restores tolerance to islet antigens. Project 1 - Genetically-Engineered Antigen-Specific Treqs to Treat Autoimmunity (Jeffrey Bluestone, PI): The principal goals of this project are: (i) to develop engineered antigen-specific Tregs by introducing autoreactive T cell receptors (TCRs) and other therapeutic genes, (ii) to assess the mechanisms and safety of cellular therapy with engineered Tregs; an (iii) to generate large quantities of autoreactive engineered Tregs capable of suppressing pathogenic autoreactive T cell responses. Project 2 - Stability and Plasticity of Treqs (Abul Abbas, PI): This project tests the hypothesis that effector T cells and Treg are not fixed lineages, but can be converted by changes in their environment. By defining the mechanisms underlying plasticity and stability, we seek to develop means to optimize cellular therapy. Pilot Project - Isolation. Expansion, and Function of Tregs in SLE (David Daikh, PI): The principal goals of this project are; (i) to determine the ability to activate and expand Tregs purified from patients with SLE; and (ii) to evaluate the functional potential of these Tregs as a foundation for potential treatment of lupus with expanded autologous Tregs. The broad aim of the ACE program at UCSF is to work collaboratively with other ACE sites to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Within this umbrella, the UCSF site will focus on interrelated aspects of Treg biology and potential clinical applications through a highly coordinated set of clinical and laboratory studies designed to bring Treg therapy from bench to bedside. CLINICAL COMPONENT (WOFSY, D) CLINICAL COMPONENT (provided by applicant): The University of California, San Francisco (UCSF) conducts clinical trials in a wide range of autoimmune diseases. This proposal focuses primarily on three of these diseases (systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes mellitus), but we also describe active programs in several other autoimmune diseases, including rheumatoid arthritis, juvenile idiopathic arthritis, ankylosing spondylitis, and scleroderma. Two concept proposals for clinical trials are presented to demonstrate our interests and our ability to develop collaborative multicenter clinical trials for patients with autoimmune diseases. The two proposed clinical trials are: Protocol 1 is a randomized, double-blind, phase Ib/IIa trial of anti-CD20 plus cyclophosphamide (IVC) as induction therapy in patients with active lupus nephritis. This trial is based on extensive, but uncontrolled, clinical series indicating that brief induction therapy with anti-CD20 plus IVC is effective in lupus nephritis and, moreover, that this combination may offer the potential to minimize chronic immune suppression. It will test the hypothesis that the use of IVC in conjunction with anti-CD20 will promote emergence of Tregs and thereby provide sustained clinical benefit. Protocol 2 is a randomized, double-blind, phase II trial of imatinib (Gleevec(r)) in patients with new-onset type I diabetes mellitus (T1DM). This trial is based on extensive pre-clinical work in our own laboratories indicating that imatinib is effective in diabetes-prone NOD mice. This trial will test the hypothesis that imatinib eliminates activated autoreactive T cells and thereby restores tolerance to islet antigens in T1DM patients. The ACE program at UCSF seeks to work collaboratively with other ACE sites to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Our programs across a broad range of diseases provide a strong foundation for such collaborations, toward this end, we have put forward two concept proposals that address important unanswered questions that could become the focus of ACE trials and mechanistic studies.

描述（由申请人提供）：本申请的中心主题是阐明调节性T细胞（Treg）在自身免疫性疾病中的作用并探索其作为治疗剂的潜力。为此，我们提出了一套重点明确、完全整合的实验室和临床研究。具体来说，我们的提案包括： 临床中心（David Wofsy，PI）：参与本申请的研究人员在开展多种自身免疫性疾病的临床试验方面拥有丰富的经验。提出了两个概念提案。方案1是抗CD20加环磷酰胺(IVC)作为活动性狼疮肾炎患者诱导治疗的Ib/IIa期试验。它将检验以下假设：IVC 与抗 CD20 联合使用将促进 Tregs 的出现，从而提供持续的临床益处。方案 2 是伊马替尼 (Gleevec(r)) 在新发 I 型糖尿病患者中的 II 期试验。该试验基于我们自己实验室的广泛临床前工作。它将检验伊马替尼消除激活的自身反应性 T 细胞并从而恢复对胰岛抗原的耐受性的假设。项目 1 - 基因工程抗原特异性 Treqs 治疗自身免疫（Jeffrey Bluestone，PI）：该项目的主要目标是：（i）通过引入自身反应性 T 细胞受体（TCR）和其他治疗基因来开发工程化抗原特异性 Tregs，（ii）评估工程化 Tregs 细胞治疗的机制和安全性； (iii)产生大量能够抑制致病性自身反应性T细胞反应的自身反应性Tregs。项目 2 - Treqs 的稳定性和可塑性（Abul Abbas，PI）：该项目测试效应 T 细胞和 Treg 不是固定谱系，而是可以通过环境变化进行转换的假设。通过定义可塑性和稳定性的机制，我们寻求开发优化细胞治疗的方法。试点项目 - 隔离。 SLE 中 Tregs 的扩展和功能（David Daikh，PI）：该项目的主要目标是； (i) 确定从 SLE 患者中纯化的 Tregs 的激活和扩增能力； (ii) 评估这些 Tregs 的功能潜力，作为利用扩增的自体 Tregs 潜在治疗狼疮的基础。 UCSF ACE 项目的总体目标是与其他 ACE 中心合作，将免疫学和分子生物学的进展转化为针对自身免疫性疾病患者的实用、安全和有效的疗法。在这个框架内，加州大学旧金山分校网站将通过一系列高度协调的临床和实验室研究，重点关注 Treg 生物学的相互关联方面和潜在的临床应用，旨在将 Treg 疗法从实验室带到临床。 临床部分（WOFSY，D） 临床部分（由申请人提供）：加州大学旧金山分校 (UCSF) 对多种自身免疫性疾病进行临床试验。该提案主要关注其中三种疾病（系统性红斑狼疮、多发性硬化症和 1 型糖尿病），但我们也描述了其他几种自身免疫性疾病的积极计划，包括类风湿性关节炎、幼年特发性关节炎、强直性脊柱炎和硬皮病。提出了两个临床试验概念提案，以展示我们为自身免疫性疾病患者开展协作多中心临床试验的兴趣和能力。拟议的两项临床试验是： 方案 1 是一项随机、双盲、Ib/IIa 期试验，抗 CD20 加环磷酰胺 (IVC) 作为活动性狼疮肾炎患者的诱导治疗。该试验基于广泛但不受控制的临床系列，表明抗 CD20 加 IVC 的短暂诱导治疗对狼疮肾炎有效，此外，这种组合可能提供最大限度减少慢性免疫抑制的潜力。它将检验以下假设：IVC 与抗 CD20 联合使用将促进 Tregs 的出现，从而提供持续的临床益处。方案 2 是一项针对新发 I 型糖尿病 (T1DM) 患者的伊马替尼 (Gleevec(r)) 随机、双盲 II 期试验。该试验基于我们自己实验室的广泛临床前工作，表明伊马替尼对易患糖尿病的 NOD 小鼠有效。该试验将检验伊马替尼消除激活的自身反应性 T 细胞，从而恢复 T1DM 患者对胰岛抗原的耐受性的假设。 UCSF 的 ACE 项目寻求与其他 ACE 中心合作，将免疫学和分子生物学的进展转化为针对自身免疫性疾病患者的实用、安全和有效的疗法。我们针对广泛疾病的项目为此类合作奠定了坚实的基础，为此，我们提出了两个概念提案，解决了可能成为 ACE 试验和机制研究焦点的重要未解答问题。