Autoimmunity Center of Excellence

自身免疫卓越中心

• 批准号: 8454524
• 负责人: David Wofsy
• 金额: $ 47.16万
• 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 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8454524
• 关键词: Address; Adult; Affect; Ankylosing spondylitis; Antigens; Area; Autoimmune Diseases; Autoimmunity; Autologous; Basic Science; Biology; California; Cessation of life; Child; Childhood; Chronic; Chronic Childhood Arthritis; Chronic Disease; Clinical; Clinical Investigator; Clinical Research; Clinical Sciences; Clinical Trials; Clinical trial protocol document; Collaborations; Community Physician; Conduct Clinical Trials; Conscious; Core Facility; Cross-Sectional Studies; Cyclophosphamide; Data; Dermatology; Diabetes Mellitus; Disease; Double-Blind Method; Endocrinologist; Endocrinology; Engineering; Environment; Finding by Cause; Foundations; Future; Genetic Engineering; Gleevec; Goals; Grant; Head; Imatinib; Immunologics; Immunology; Immunosuppression; Inbred NOD Mice; Individual; Insulin-Dependent Diabetes Mellitus; Investigation; Laboratories; Laboratory Study; Lead; Leadership; Lupus; Lupus Nephritis; MS4A1 gene; Medicine; Mentors; Modeling; Molecular Biology; Multiple Sclerosis; Neoadjuvant Therapy; Neurology; Operative Surgical Procedures; Organ; Participant; Pathology; Patient Care; Patients; Pediatrics; Phase; Phase II Clinical Trials; Pilot Projects; Play; Population; Protocols documentation; Randomized; Regulatory T-Lymphocyte; Research; Research Activity; Research Design; Research Personnel; Rheumatoid Arthritis; Rheumatology; Role; Safety; San Francisco; Scientist; Scleroderma; Series; Site; Systemic Lupus Erythematosus; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic Agents; Translating; Translational Research; United States; Universities; Wegener' s Granulomatosis; Work; autoreactive T cell; base; bench to bedside; clinical application; design; effective therapy; experience; innovation; interest; islet; next generation; novel; novel therapeutics; pre-clinical; programs; rheumatologist; therapeutic gene

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，我们提出了一个紧密集中，完全集成的实验室和临床研究。具体而言，我们的提案包括：临床中心（大卫沃夫西，PI）：参与本申请的研究者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是抗CD 20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。本研究将检验IVC联合抗CD 20治疗将促进T细胞减少症的出现，从而提供持续临床获益的假设。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。这项试验是基于我们自己实验室的广泛临床前工作。它将测试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的抗原特异性T细胞受体，（ii）评估工程化T细胞受体的细胞治疗机制和安全性;和（iii）产生大量能够抑制致病性自身反应性T细胞应答的自身反应性工程化T细胞。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，但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TCLs的扩增和功能（大卫戴克，PI）：该项目的主要目标是：（i）确定活化和扩增从SLE患者纯化的TCLs的能力;和（ii）评估这些TCLs的功能潜力，作为用扩增的自体TCLs治疗狼疮的潜在基础。 UCSF ACE项目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自身免疫性疾病患者的实用，安全和有效的疗法。在此框架内，加州大学旧金山分校的研究中心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治疗从实验室带到床边。 临床组件（WOFSY，D） 临床组成部分（由申请人提供）：加州大学弗朗西斯科分校（UCSF）在广泛的自身免疫性疾病中进行临床试验。本建议主要集中在这些疾病（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，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的积极计划。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的能力，为自身免疫性疾病患者开展协作多中心临床试验。方案1是一项随机、双盲、Ib/IIa期试验，抗CD 20+环磷酰胺（IVC）作为活动性狼疮肾炎患者的诱导治疗。这项试验是基于广泛的，但不受控制的，临床系列表明，短暂的诱导治疗与抗CD 20加IVC是有效的狼疮肾炎，而且，这种组合可能会提供最大限度地减少慢性免疫抑制的潜力。本研究将检验IVC联合抗CD 20治疗将促进T细胞减少症的出现，从而提供持续临床获益的假设。方案2是一项伊马替尼（Gleevec（r））治疗新发I型糖尿病（T1 DM）患者的随机、双盲、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，表明伊马替尼对糖尿病易感NOD小鼠有效。该试验将检验伊马替尼消除活化的自身反应性T细胞，从而恢复T1 DM患者对胰岛抗原的耐受性的假设。 UCSF的ACE项目旨在与其他ACE站点合作，将免疫学和分子生物学的进展转化为自身免疫性疾病患者的实用，安全和有效的疗法。我们在广泛疾病领域的项目为这种合作提供了坚实的基础，为此，我们提出了两个概念提案，解决了可能成为ACE试验和机制研究重点的重要未回答问题。

项目成果

Cutting edge: Self-antigen controls the balance between effector and regulatory T cells in peripheral tissues.

• DOI: 10.4049/jimmunol.1301777
• 发表时间: 2014-02-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Gratz IK;Rosenblum MD;Maurano MM;Paw JS;Truong HA;Marshak-Rothstein A;Abbas AK
• 通讯作者: Abbas AK

Crossing the Atlantic: the Euro-Lupus Nephritis regimen in North America.

• DOI: 10.1002/art.39067
• 发表时间: 2015-05
• 期刊: Arthritis & rheumatology (Hoboken, N.J.)
• 作者: Wofsy D;Diamond B;Houssiau FA
• 通讯作者: Houssiau FA