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: 6802803
• 负责人: David Wofsy
• 金额: $ 82.02万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6802803
• 关键词: autoimmune disorder; autoimmunity; clinical research; cooperative study; human subject

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)： 这项应用的广泛目标是将免疫学和分子生物学的进展转化为对自身免疫性疾病患者实用、安全和有效的治疗。为此，我们将参与新型免疫疗法的合作临床试验，并将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议由一个临床中心、两个基础研究项目和一个免疫功能监测核心组成，如下所述：临床中心(David Wofsy，PI)。参与这一应用的研究人员在进行各种自身免疫性疾病的临床试验方面拥有丰富的经验。该应用主要针对系统性红斑狼疮(SLE)、多发性硬化症(MS)和I型糖尿病(IDDM)。两个临床方案被提出，都是基于这项提案的参与者在加州大学旧金山分校进行的基础研究。方案1是基于观察到，阻断CTLA4Ig对T细胞的共刺激，与环磷酰胺的常规治疗相结合，对小鼠狼疮产生长期的益处。它验证了这样一种假设，即这种治疗方法对狼疮性肾炎患者有效。方案2是基于观察到HMG-CoA抑制剂(他汀类药物)延缓MS的小鼠模型，它测试了阿托伐他汀将防止高危患者进展为MS的假设。 项目1-调节性T淋巴细胞的激活和功能(阿布·阿巴斯和杰弗里·布鲁斯通，共同PI)：本项目的主要目标是：(1)阐明调节性T细胞(Treg)的诱导和维持所涉及的信号；以及(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的小鼠模型来阐明疾病的机制，并了解特定治疗干预措施的有效性的基础；以及(2)开发新的抗原特异性方法来治疗小鼠模型中的自身免疫性疾病，作为人类临床试验的前奏。 免疫功能监测核心(Lawrence Fong，PI)：这一核心设施将提供开发和对样本(例如血液、淋巴结等)进行细胞和基于抗体的免疫分析的能力。源自参与ACE试验的患者。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；细胞因子的酶联免疫吸附试验、ELISPOT和FLOW分析；T细胞增殖；以及细胞毒性试验。这一核心将支持临床中心和项目2。临床中心、个别项目和免疫监测核心共同组成一个紧密联系的计划，将新的治疗方法从工作台带到床边，并调查这些治疗方法延缓自身免疫性疾病的机制。