Autoimmunity Center of Excellence

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，并探索其作为治疗药物的潜力。为此，我们提出了一套紧密聚焦的、完全整合的实验室和临床研究。具体而言，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各种自身免疫性疾病的临床试验方面具有丰富的经验。提出了两个概念建议。方案1是一项Ib/lla期试验，抗cd20 +环磷酰胺（IVC）作为诱导治疗治疗活动性狼疮性肾炎患者。它将验证IVC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（格列卫）在新发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大量临床前工作。它将测试假设伊马替尼消除活化的自身反应性T细胞，从而恢复对胰岛抗原的耐受性。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（TCRs）和其他治疗基因来开发工程抗原特异性Tregs， （ii）评估工程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细胞反应的自反应性工程Tregs。项目2 - treq的稳定性和可塑性（Abul Abbas， PI）：该项目验证了效应T细胞和Treg不是固定谱系的假设，但可以通过环境的变化进行转换。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。试验项目-隔离。Tregs在SLE中的扩展和功能（David Daikh， PI）：该项目的主要目标是；(i)确定激活和扩增从SLE患者纯化的treg的能力；（ii）评估这些treg的功能潜力，作为扩展自体treg治疗狼疮的潜在基础。

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.