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（由申请人提供）：斯坦福ACE将支持一项综合基础和临床研究计划，该计划侧重于耐受性诱导和免疫调节，以预防或治疗自身免疫性疾病。斯坦福自身免疫卓越中心（中心）的主要主题是研究CD4 T细胞在自身免疫性疾病的发病机理和治疗中的调节。该中心将得到美国其他ACE群体的支持和支持；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记录的领导力。该中心的成功将得到先前在斯坦福大学（Stanford）的相互关系的支持，这些科学家的多个部门的临床医生中，研究了多个器官和组织中的自身免疫性疾病。斯坦福ACE将由斯坦福医学院多个学科的出色基础和临床研究人员组成，并提出了一个基础研究项目，以CD4 T细胞的不反应性为中心，以及一个研究新的T细胞谱系（称为TH17细胞）的翻译研究项目，这些淋巴细胞均为这些淋巴细胞的能力来表征（IL-17）。拟议的临床研究项目包括三种不同的自身免疫性疾病[弥漫性全身性硬化症（SSC），银屑病关节炎和全身性少年特发性关节炎（SJIA）]，使成人和儿童以及有机系统以及既有效率又会构成既定的机制，以及既有效率的机制，y。治疗学。拟议的飞行员和可行性项目提出了针对全身少年特发性关节炎（SJIA）患者进行两年研究计划，以识别和验证尿液肽生物标志物，以预测（a）对TNF抑制作用的反应； （b）对IL-1抑制作用的反应； （c）即将发生的疾病耀斑。此外，该提案将为其他ACE群体提供访问最先进的试剂和技术平台，以研究人类自身免疫性疾病，并传播其他ACE的教育材料，这些材料可被其他ACE用于向高中，本科，研究生，研究生以及临床和临床研究员和临床研究员教授临床免疫学概念。 斯坦福大学提议通过提出并对CD4 T细胞不反应的机制进行基本和转化研究来支持综合基础，临床和临床研究；两项临床试验，包括对自身免疫性疾病的这些疗法的新疗法和机械研究；以及一项试图发展新的疾病的试点建议。 项目1A：临床组件（Genovese，M） 临床成分描述（由申请人提供）：斯坦福大学医学中心（SUMC）具有医学，转化和基础科学研究的非凡传统。将有一系列出色的资源，教职员工和设施来支持斯坦福大学拟议的ACE网站。该提案汇集了一群熟练的翻译研究人员，这些研究人员在实验室和临床研究中都具有生产力的记录，重点是人类自身免疫性介导的疾病。斯坦福大学汇集了各种学科，以证明成就和与以下领域的合作能力：成人风湿病学，皮肤病学，肺医学和儿科风湿病学。为此提出的项目选择的项目强调了风湿病学（成人和小儿），皮肤病学和肺医学之间存在的重要合作。这两个临床试验项目均探索诸如银屑病关节炎和全身性硬化症等疾病的皮肤病学和风湿病表现。临床试验概念1：使用抗IL-17 MAB在主动牛皮癣关节炎治疗中的主要假设：在活跃的牛皮利亚关节炎（PSA）受试者中，从基线到第14周的ACR 20反应的患者比例在IL-17 MAB治疗的受试者中，该目标是从基准方面的AIL AIRS AIRS A A IS A IS A IS A IS A A I is A IS A A I is A IS A IS A A I is A IS A A I is A IS A A I is A Is A Issbootion进行的： Lnterleukin-17（IL-17 MAB）单克隆抗体在用活性皮肤和关节疾病治疗PSA方面的安全性和功效。 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细胞因子谱将与临床反应有关。目的：这项研究的主要目的是确定CTLA-4LG（Abatacept）的安全性和功效，用于治疗DSSC相关性皮肤表现（请参阅说明）：斯坦福大学ACE将支持综合基础和临床研究计划，该计划侧重于耐受性诱导和免疫调节，以预防或治疗自动疾病（AL）疾病。斯坦福ACE提出了临床研究项目，该项目包括三种不同的自身免疫性疾病（SSC，银屑病关节炎和SJIA），并提议研究用于预防或治疗不同AL疾病的治疗疗法的MOA。