UCSF Autoimmunity Center of Excellence

加州大学旧金山分校自身免疫卓越中心

• 批准号: 7227484
• 负责人: David Wofsy
• 金额: $ 84.11万
• 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 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7227484
• 关键词: 3-hydroxy-3-methylglutaryl-coenzyme A; Antibodies; Antigen Targeting; Antigens; Autoimmune Diseases; Autoimmunity; Basic Science; Biological Assay; Blood; Clinical; Clinical Protocols; Clinical Trials; Conduct Clinical Trials; Core Facility; Cyclophosphamide; Disease; Effector Cell; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Goals; Human; Immune; Immunologic Monitoring; Immunology; Immunotherapy; Individual; Insulin-Dependent Diabetes Mellitus; Lead; Link; Lupus; Lupus Nephritis; Maintenance; Modeling; Molecular Biology; Monitor; Multiple Sclerosis; Mus; Participant; Patients; Peptide/MHC Complex; Production; Protocols documentation; Regulatory T-Lymphocyte; Research Personnel; Research Project Grants; Risk; Sampling; Signal Transduction; Staining method; Stains; Systemic Lupus Erythematosus; T-Cell Proliferation; T-Lymphocyte; Testing; Therapeutic Intervention; Translating; atorvastatin; base; bench to bedside; cytokine; cytotoxicity; enzyme linked immunospot assay; experience; immune function; inhibitor/antagonist; lymph nodes; novel; prevent; programs

DESCRIPTION (provided by applicant): The broad aim of this application is to translate advances in immunology and molecular biology into practical, safe, and effective therapies for people with autoimmune diseases. Toward this end, we will participate in collaborative clinical trials of novel immunotherapies, and we will conduct basic research into the mechanisms that lead to autoimmunity as well as the mechanisms that can be harnessed to prevent autoimmunity. This proposal to become an Autoimmunity Center of Excellence consists of a Clinical Center, two basic research projects, and an Immune Function Monitoring Core as described below: Clinical Center (David Wofsy, PI). Investigators involved in this application have extensive experience in the conduct of clinical trials in diverse autoimmune diseases. This application focuses primarily on systemic lupus erythematosus (SLE), multiple sclerosis (MS), and type I diabetes mellitus (IDDM). Two clinical protocols are proposed, both based on basic research conducted at UCSF by participants in this proposal. Protocol 1 is based on the observation that blockade of T cell co-stimulation by CTLA4Ig, in combination with conventional therapy with cyclophosphamide, produces long-lasting benefit in murine lupus. It tests the hypothesis that this approach to therapy will be effective in people with lupus nephritis. Protocol 2 is based on the observation that HMG-CoA inhibitors ('statins') retard murine models for MS. It tests the hypothesis that atorvastatin will prevent progression to MS in patients at high risk. Project 1 - Activation and functions of regulatory T lymphocytes (Abul Abbas and Jeffrey Bluestone, co-PIs): The principal goals of this project are: (1) to clarify the signals involved in the induction and maintenance of regulatory T cells (Treg); and (2) to understand the mechanisms by which Treg control potentially pathogenic effector cells. Project 2 - Targeting antigen-specific T cells in SLE (David Daikh, PI): The principal goals of this project are: (1) to use murine models for SLE to clarify the mechanisms of disease, and to understand the basis for the efficacy of specific therapeutic interventions; and (2} to develop novel antigen-specific approaches to the treatment of autoimmune disease in murine models as a prelude to clinical trials in humans. Immune Function Monitoring Core (Lawrence Fong, PI): This core facility will provide the capability for developing and performing cellular and antibody-based immune assays on samples (e.g., blood, lymph node, etc.) derived from patients participating in ACE trials. Assays that will be available include: flow cytometry; MHC/peptide tetramer production and staining; cytokine analysis by ELISA, ELISPOT, and flow; T cell proliferation; and cytotoxicity assays. This core will support the Clinical Center and Project 2. Together, the Clinical Center, individual projects, and Immune Monitoring Core comprise a tightly linked program to bring novel therapies from bench to bedside and to investigate the mechanisms by which these therapies retard autoimmune disease.

描述（由申请人提供）： 该应用的广泛目标是将免疫学和分子生物学的进步转化为针对自身免疫性疾病患者的实用、安全和有效的疗法。为此，我们将参与新型免疫疗法的合作临床试验，并对导致自身免疫的机制以及可用于预防自身免疫的机制进行基础研究。这项成为自身免疫卓越中心的提案包括一个临床中心、两个基础研究项目和一个免疫功能监测核心，如下所述：临床中心（David Wofsy，PI）。参与本申请的研究人员在开展多种自身免疫性疾病的临床试验方面拥有丰富的经验。该应用主要关注系统性红斑狼疮 (SLE)、多发性硬化症 (MS) 和 I 型糖尿病 (IDDM)。提出了两个临床方案，均基于该提案参与者在加州大学旧金山分校进行的基础研究。 方案 1 基于这样的观察：CTLA4Ig 阻断 T 细胞共刺激，与环磷酰胺的常规疗法相结合，可对小鼠狼疮产生持久的益处。它检验了这种治疗方法对狼疮性肾炎患者有效的假设。方案 2 基于 HMG-CoA 抑制剂（“他汀类药物”）延迟 MS 小鼠模型的观察。 它检验了阿托伐他汀可以预防高危患者进展为多发性硬化症的假设。 项目1——调节性T淋巴细胞的激活和功能（Abul Abbas和Jeffrey Bluestone，共同PI）：该项目的主要目标是：（1）阐明调节性T细胞（Treg）诱导和维持所涉及的信号； (2) 了解 Treg 控制潜在致病效应细胞的机制。 项目2——针对SLE中的抗原特异性T细胞（David Daikh，PI）：该项目的主要目标是：（1）使用SLE小鼠模型来阐明疾病机制，并了解特定治疗干预措施功效的基础； (2) 在小鼠模型中开发新的抗原特异性方法来治疗自身免疫性疾病，作为人类临床试验的前奏。 免疫功能监测核心（Lawrence Fong，PI）：该核心设施将提供对来自参与 ACE 试验的患者的样本（例如血液、淋巴结等）开发和执行基于细胞和抗体的免疫测定的能力。可用的检测方法包括：流式细胞术； MHC/肽四聚体的产生和染色；通过 ELISA、ELISPOT 和流式细胞仪进行细胞因子分析； T细胞增殖；和细胞毒性测定。该核心将支持临床中心和项目 2。临床中心、各个项目和免疫监测核心共同构成一个紧密相连的计划，将新疗法从实验室带到临床，并研究这些疗法延缓自身免疫性疾病的机制。