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）：斯坦福大学ACE将支持一项综合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（中心）的主要主题是研究CD 4 T细胞在自身免疫性疾病发病机制和治疗中的调节。该中心将支持并得到美国其他ACE团体的支持;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的有据可查的领导地位。该中心的成功将得到先前在斯坦福大学建立的来自多个部门的临床科学家之间的相互关系的支持，这些科学家研究多个器官和组织中的自身免疫性疾病。斯坦福大学ACE将由来自斯坦福大学医学院多个学科的优秀基础和临床研究人员组成，并提出了一个基础研究项目，以CD 4 T细胞无反应性为中心，和一个研究新的T细胞谱系的转化研究项目Th 17细胞的特征在于这些淋巴细胞能够分泌高水平的促炎细胞因子白细胞介素-17（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[弥漫性系统性硬化症（SSc），银屑病关节炎和全身性青少年特发性关节炎（SJIA）]，这些疾病折磨成人和儿童，以及器官系统，包括关节，皮肤，血液成分和血管，并将测试治疗的疗效，并开发测试来表征这些疗法的作用机制。拟议的试点和可行性项目提出了一项为期两年的系统性幼年特发性关节炎（SJIA）患者研究计划，以确定和验证预测（a）对TNF抑制的反应;（B）对IL-1抑制的反应;和（c）即将发生的疾病发作的尿肽生物标志物。此外，该提案将为其他ACE团体提供研究人类自身免疫性疾病的尖端试剂和技术平台，并传播可供其他ACE用于向高中，本科生，研究生，研究生和临床研究员和教师教授临床免疫学概念的教育材料。 斯坦福大学ACE建议通过提出并开展对CD 4 T细胞无反应机制的基础和转化研究，支持综合基础、临床前和临床研究;两项临床试验，包括新疗法和这些疗法治疗自身免疫性疾病的机制研究;以及一项旨在开发新的疾病生物标志物的试点提案。 项目1A：临床组件（Genovese，M） 临床组件描述（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。一系列优秀的资源，教师和设施将可用于支持拟议的ACE网站在斯坦福大学。该提案汇集了一批技术熟练的翻译研究人员，他们在实验室和临床研究中的生产力记录都集中在人类自身免疫介导的疾病上。斯坦福大学汇集了各种学科，以展示与以下领域合作的成就和能力：成人流变学，皮肤病学，肺医学和儿科流变学。本次申报选择的项目突出了风湿病学（成人和儿科）、皮肤病学和肺医学之间的重要合作。这两个临床试验项目都探索了银屑病关节炎和系统性硬化症等疾病的皮肤病学和风湿病学表现。临床试验概念1：使用抗IL-17单抗治疗活动性银屑病关节炎主要假设：在接受IL-17单抗治疗的活动性银屑病关节炎（PSA）受试者中，从基线至第14周达到ACR 20应答的患者比例大于接受安慰剂治疗的活动性PSA受试者中从基线至第14周达到ACR 20应答的患者比例。本研究的目的是确定白细胞介素-17单克隆抗体（IL-17 mAb）治疗活动性皮肤和关节疾病的PsA的安全性和有效性。临床试验概念2：CTLA-4 Ig的使用（阿巴西普）在弥漫性系统性硬化症受试者中的应用鉴于支持活化T细胞在受影响皮肤中的作用的几条证据，我们假设抑制T细胞活化可能导致弥漫性系统性硬化症（dSSc）患者皮肤表现的显著临床改善，并且组织和血液自身抗体和细胞因子谱的变化将与临床应答相关。目的：本研究的主要目的是确定CTLA-4lg（阿巴西普）治疗dSSc皮肤表现的安全性和有效性相关性（参见说明书）：斯坦福大学ACE将支持一项综合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（AI）疾病。斯坦福大学ACE提出了包括三种不同的自身免疫性疾病（SSc、银屑病关节炎和SJIA）的临床研究项目，并提出研究用于预防或治疗不同Al疾病的治疗剂的MoA。