Autoimmunity Center of Excellence (ACE) at Stanford

斯坦福大学自身免疫卓越中心 (ACE)

• 批准号: 7846553
• 负责人: CHARLES GARRISON FATHMAN
• 金额: $ 4.93万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-05 至 2010-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7846553
• 关键词: Autoimmunity; Center; Excellence; ACE; Stanford

DESCRIPTION (provided by applicant): The Stanford ACE will support an integrated basic and clinical research program focused on tolerance induction and immune modulation to prevent or treat autoimmune disease. The major theme of the Stanford Autoimmunity Center of Excellence (the Center) is the study of the regulation of CD4 T cells in pathogenesis and treatment of autoimmune diseases. The Center will support and be supported by other ACE groups across the United States; and will take advantage of Stanford's documented leadership in basic and clinical research, technology development, and education in clinical immunology. Success of the Center will be supported by the interrelationships previously established at Stanford among clinician scientists from multiple departments studying autoimmune diseases in multiple organs and tissues. The Stanford ACE will be composed of outstanding basic and clinical investigators from multiple disciplines at Stanford Medical School and proposes both a basic Research Project, centered on CD4 T cell unresponsiveness, and a translational Research Project to study a new T cell lineage (termed Th17 cells) that is characterized by the ability of these lymphocytes to secrete high levels of the proinflammatory cytokine interleukin-17 (IL-17). Proposed clinical research projects encompass three different autoimmune diseases [diffuse systemic sclerosis (SSc), psoriatic arthritis and systemic juvenile idiopathic arthritis (SJIA)] that afflict adults and children, as well as organ systems including joints, skin, blood elements, and blood vessels, and will both test efficacy of therapy and develop tests to characterize the mechanisms of action of these therapeutics. The proposed Pilot and Feasibility Project proposes a two year research plan in Systemic Juvenile Idiopathic Arthritis (SJIA) patients to identify and validate urine peptide biomarkers that predict (a) response to TNF inhibition; (b) response to IL-1 inhibition; and (c) impending disease flare. In addition, this proposal will provide other ACE groups access to cutting edge reagents and technology platforms for studying human autoimmune diseases, and dissemination of Educational Materials that can be used by other ACEs to teach clinical immunology concepts to high school, undergraduate, graduate, postgraduate, and clinical fellows and faculty. The Stanford ACE proposes to support integrated basic, pre-clinical and clinical research by proposing and then conducting basic and translational research into the mechanism of CD4 T cell unresponsiveness; two clinical trials that include novel therapies and mechanistic studies of these therapies for autoimmune diseases; and a pilot proposal that intends to develop new bi omarkers of disease. PROJECT 1A: Clinical Component (Genovese, M) CLINICAL COMPONENT DESCRIPTION (provided by applicant): Stanford University Medical Center (SUMC) has an extraordinary tradition of medical, translational, and basic science research. An outstanding array of resources, faculty, and facilities will be available to support the proposed ACE site at Stanford University. This proposal brings together a skilled group of translational researchers with a track record of productivity in both laboratory and clinical research focusing on human autoimmune mediated diseases. Stanford has brought together various disciplines to demonstrate both accomplishment and ability to work together with the following fields represented: Adult Rheumatology, Dermatology, Pulmonary Medicine, and Pediatric Rheumatology. The projects chosen for this submission highlight the significant collaborations that exist between Rheumatology (Adult and Pediatric), Dermatology and Pulmonary Medicine. Both clinical trials projects explore dermatologic and rheumatologic manifestations of diseases such as Psoriatic arthritis and Systemic Sclerosis. Clinical Trial Concept 1: The use of an anti- IL-17 mab in the treatment of active Psoriatic Arthritis Primary Hypothesis: The proportion of patients achieving the ACR 20 response from Baseline to Week 14 among active Psoriatic Arthritis (PSA) subjects treated with IL-17 mab is larger than the proportion achieving ACR 20 response from Baseline to Week 14 among active PSA subjects treated with placebo Objectives: The goal of this study is to determine the safety and efficacy of a monoclonal antibody to lnterleukin-17 (IL-17 mab) in the treatment of PsA with active skin and joint disease. Clinical Trial Concept 2: The use of CTLA-4lg (abatacept) in subjects with diffuse systemic sclerosis Primary hypothesis: Given several lines of evidence supporting the role of activated T cells in affected skin, we hypothesize that inhibiting T cell activation may lead to significant clinical improvement in skin manifestations in patients with diffuse systemic sclerosis (dSSc), and that changes in tissue and blood autoantibody and cytokine profiles will be associated with clinical response. Objectives: The primary goal of this study is to determine the safety and efficacy of CTLA-4lg (Abatacept) for the treatment of cutaneous manifestations of dSSc RELEVANCE (See instructions): The Stanford ACE will support an integrated basic and clinical research program focused on tolerance induction and immune modulation to prevent or treat autoimmune (Al) disease. The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases.

描述(由申请者提供)：斯坦福大学ACE将支持一个综合的基础和临床研究计划，重点是耐受诱导和免疫调节，以预防或治疗自身免疫性疾病。斯坦福大学自身免疫卓越中心的主要主题是研究CD4T细胞在自身免疫性疾病发病机制和治疗中的调节作用。该中心将支持和得到美国其他ACE组织的支持，并将利用斯坦福大学在基础和临床研究、技术开发和临床免疫学教育方面有据可查的领导地位。该中心的成功将得到以前在斯坦福大学建立的临床科学家之间的相互关系的支持，这些科学家来自多个部门，研究多个器官和组织中的自身免疫性疾病。斯坦福ACE将由来自斯坦福医学院多个学科的杰出基础和临床研究人员组成，并提出以CD4T细胞无反应为中心的基础研究项目和研究一种新的T细胞谱系(称为Th17细胞)的翻译研究项目，其特征是这些淋巴细胞能够分泌高水平的促炎细胞因子白介素17(IL-17)。拟议的临床研究项目涵盖三种不同的自身免疫性疾病[弥漫性系统性硬化症(SSC)、牛皮癣关节炎和系统性幼年特发性关节炎(SJIA)]，这些疾病折磨着成人和儿童，以及关节、皮肤、血液元素和血管等器官系统，并将测试治疗效果和开发测试，以表征这些治疗的作用机制。拟议的试点和可行性项目提出了一项为期两年的研究计划，用于系统性青少年特发性关节炎(SJIA)患者，以确定和验证尿肽生物标志物，这些生物标志物可以预测(A)对肿瘤坏死因子抑制的反应；(B)对IL-1抑制的反应；以及(C)即将到来的疾病爆发。此外，这项提议将使其他ACE小组能够获得研究人类自身免疫性疾病的尖端试剂和技术平台，并传播其他ACE可以用来向高中、本科生、研究生、研究生和临床研究员和教职员工教授临床免疫学概念的教育材料。 斯坦福大学ACE建议支持综合基础、临床前和临床研究，方法是提出并随后对CD4T细胞无应答机制进行基础研究和转化性研究；两项临床试验，包括针对自身免疫性疾病的新疗法和这些疗法的机制研究；以及一项旨在开发新的疾病双标记物的试点提案。 项目1A：临床部分(Genovese，M) 临床成分描述(由申请人提供)：斯坦福大学医学中心(SUMC)在医学、翻译和基础科学研究方面具有非凡的传统。一批优秀的资源、师资和设施将可用于支持拟议中的斯坦福大学ACE选址。这项建议汇集了一批技术熟练的翻译研究人员，他们在专注于人类自身免疫介导性疾病的实验室和临床研究方面有着卓有成效的记录。斯坦福大学汇集了不同的学科，展示了与以下领域合作的成就和能力：成人风湿病、皮肤病、肺内科和儿科风湿病。为本报告选择的项目突出了风湿科(成人和儿科)、皮肤科和肺部医学之间存在的重要合作。这两个临床试验项目都探索银屑病关节炎和系统性硬化症等疾病的皮肤病和风湿病表现。临床试验概念1：在活动期银屑病关节炎的治疗中使用抗IL-17单抗初步假设：在接受IL-17单抗治疗的活动期银屑病(PSA)患者中，从基线到第14周达到ACR 20反应的患者比例大于接受安慰剂治疗的活动PSA患者从基线到第14周达到ACR 20反应的比例。目的：本研究的目的是确定白介素17(IL-17 MAb)在治疗伴有活动期皮肤和关节疾病的PSA中的安全性和有效性。临床试验概念2：CTLA-4LG(Abatacept)在弥漫性系统性硬化症患者中的应用初步假设：鉴于有多条证据支持激活的T细胞在受影响皮肤中的作用，我们假设抑制T细胞激活可能导致弥漫性系统性硬化症(DSSC)患者皮肤症状的显著改善，并且组织和血液中自身抗体和细胞因子谱的变化将与临床反应相关。目的：这项研究的主要目标是确定CTLA-4LG(Abatacept)治疗与皮肤干细胞相关的皮肤表现的安全性和有效性(见说明书)：斯坦福ACE将支持一项专注于耐受诱导和免疫调节的综合基础和临床研究计划，以预防或治疗自身免疫性(AL)疾病。斯坦福大学ACE提出了涵盖三种不同自身免疫性疾病(SSc、牛皮癣关节炎和SJIA)的临床研究项目，并建议研究预防或治疗不同AL疾病的疗法的MOA。