Autoimmunity Center of Excellence

描述(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，我们提出了一套紧密聚焦、完全整合的实验室和临床研究。具体地说，我们的建议包括：临床中心(David Wofsy，PI)：参与这一应用的研究人员在进行各种自身免疫性疾病的临床试验方面拥有丰富的经验。提出了两个概念性建议。方案1是抗CD20联合环磷酰胺(IVC)作为活动性狼疮性肾炎患者诱导治疗的Ib/Ila期试验。它将检验下腔静脉与抗CD20联合使用将促进Treg的出现从而提供持续的临床益处的假设。方案2是伊马替尼(Gleevec(R))在新发的I型糖尿病患者中的II期试验。这项试验是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，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 Blustone，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基因工程抗原特异性Treg，(Ii)评估利用工程Treg进行细胞治疗的机制和安全性，以及(Iii)产生大量能够抑制病理性自身反应T细胞反应的自身反应工程Treg。项目2-Treqs的稳定性和可塑性(Abu Abbas，Pi)：这个项目测试了这样一个假设，即效应器T细胞和Treg不是固定的谱系，而是可以通过环境的变化来转换的。通过定义可塑性和稳定性的潜在机制，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)确定激活和扩展从SLE患者中纯化的Tregs的能力；以及(Ii)评估这些Tregs的功能潜力，作为扩大自体Tregs治疗狼疮的潜在基础。 加州大学旧金山分校的ACE计划的广泛目标是与其他ACE站点合作，将免疫学和分子生物学的进展转化为对自身免疫性疾病患者的实用、安全和有效的治疗。在这一框架内，加州大学旧金山分校的网站将通过一系列高度协调的临床和实验室研究，专注于Treg生物学的相互关联的方面和潜在的临床应用，旨在将Treg疗法从工作台带到床边。 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)在一系列自身免疫性疾病中进行临床试验。这项建议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方案，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的概念建议，以证明我们的兴趣和我们为自身免疫性疾病患者开发协作性多中心临床试验的能力。这两项拟议的临床试验是：方案1是一项随机、双盲、Ib/IIa期试验，将抗CD20加环磷酰胺(IVC)作为活动性狼疮性肾炎患者的诱导疗法。这项试验是基于广泛但非对照的临床系列，表明抗CD20联合IVC的短期诱导治疗对狼疮性肾炎有效，而且，这种联合治疗可能提供将慢性免疫抑制降至最低的可能性。它将检验下腔静脉与抗CD20联合使用将促进Treg的出现从而提供持续的临床益处的假设。方案2是伊马替尼(Gleevec(R))在新发的I型糖尿病(T1 DM)患者中的随机、双盲、II期试验。这项试验是基于我们自己实验室的大量临床前工作，表明伊马替尼对易患糖尿病的NOD小鼠有效。这项试验将验证伊马替尼消除激活的自身反应性T细胞，从而恢复T1 DM患者对胰岛抗原的耐受性的假设。 加州大学旧金山分校的ACE计划寻求与其他ACE网站合作，将免疫学和分子生物学的进步转化为对自身免疫性疾病患者实用、安全和有效的治疗方法。我们涵盖广泛疾病的项目为此类合作提供了坚实的基础，为此，我们提出了两个概念建议，以解决可能成为ACE试验和机械学研究重点的重要悬而未决的问题。

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.