Autoimmunity Center of Excellence (ACE) at Stanford

斯坦福大学自身免疫卓越中心 (ACE)

• 批准号: 7798610
• 负责人: CHARLES GARRISON FATHMAN
• 金额: $ 70.1万
• 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: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7798610
• 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项目，重点关注耐受诱导和免疫调节，以预防或治疗自身免疫性疾病。斯坦福自身免疫卓越中心（以下简称“中心”）的主要主题是研究 CD4 T 细胞在自身免疫性疾病发病机制和治疗中的调节作用。该中心将支持全美其他 ACE 团体，并得到其支持；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公认的领导地位。该中心的成功将得到斯坦福大学先前在研究多个器官和组织自身免疫性疾病的多个部门的临床科学家之间建立的相互关系的支持。斯坦福大学 ACE 将由来自斯坦福大学医学院多个学科的杰出基础和临床研究人员组成，提出一个以 CD4 T 细胞无反应为中心的基础研究项目，以及一个研究新 T 细胞谱系（称为 Th17 细胞）的转化研究项目。 ）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细胞介素-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）、银屑病关节炎和系统性幼年特发性关节炎（SJIA）]，这些疾病困扰成人和儿童，以及包括关节、皮肤、血液成分和血管在内的器官系统，并将测试疗法的功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针对系统性幼年特发性关节炎 (SJIA) 患者的为期两年的研究计划，以识别和验证尿肽生物标志物，以预测 (a) 对 TNF 抑制的反应； (b) 对 IL-1 抑制的反应； (c) 即将发生的疾病爆发。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，并传播其他 ACE 可以用来向高中、本科生、研究生、研究生教授临床免疫学概念的教育材料。以及临床研究员和教职人员。 斯坦福大学 ACE 提议通过提出并开展 CD4 T 细胞无反应机制的基础和转化研究来支持基础、临床前和临床的综合研究；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生物标志物的试点提案。 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) 拥有非凡的医学、转化和基础科学研究传统。斯坦福大学将提供一系列优秀的资源、师资和设施来支持拟议的 ACE 站点。该提案汇集了一批技术精湛的转化研究人员，他们在专注于人类自身免疫介导疾病的实验室和临床研究方面拥有出色的生产力记录。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：成人风湿病学、皮肤病学、肺病学和儿童风湿病学。本次提交的项目强调了风湿病学（成人和儿童）、皮肤病学和肺病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学和风湿病学表现。临床试验概念 1：使用抗 IL-17 mab 治疗活动性银屑病关节炎 主要假设：在接受 IL 治疗的活动性银屑病关节炎 (PSA) 受试者中，从基线到第 14 周达到 ACR 20 缓解的患者比例-17 mab 大于接受安慰剂治疗的活跃 PSA 受试者中从基线到第 14 周实现 ACR 20 反应的比例 目的：本研究的目标是确定白细胞介素 17 单克隆抗体 (IL-17 mab) 治疗患有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-4lg（阿巴西普）在弥漫性系统性硬化症受试者中的使用 主要假设：鉴于支持活化 T 细胞在受影响皮肤中的作用的多项证据，我们假设抑制 T 细胞活化可能会导致显着的弥漫性系统性硬化症（dSSc）患者皮肤表现的临床改善，组织和血液自身抗体和细胞因子谱的变化将与临床反应相关。目的：本研究的主要目标是确定 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）：斯坦福大学 ACE 将支持一项综合基础和临床研究计划，重点关注耐受诱导和免疫调节以预防或治疗自身免疫（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、银屑病关节炎和 SJIA）的临床研究项目，并提议研究预防或治疗不同 Al 疾病的治疗方法 MoA。