UCSF Autoimmunity Center of Excellence

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展转化为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。本提案旨在成为一个自身免疫卓越中心，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（大卫沃夫西，PI）。参与本申请的研究者在各种自身免疫性疾病的临床试验中具有丰富的经验。这种应用主要集中在系统性红斑狼疮（SLE），多发性硬化症（MS）和I型糖尿病（IDDM）。两个临床协议提出，都是基于在UCSF进行的基础研究参与者在这个建议。 方案1是基于以下观察结果：CTLA 4 Ig阻断T细胞共刺激，与环磷酰胺常规治疗组合，在鼠狼疮中产生持久的益处。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”）延缓MS小鼠模型的观察结果。它检验了阿托伐他汀将预防高危患者进展为MS的假设。 项目1 -调节性T淋巴细胞的激活和功能（Abul Abbas和Jeffrey Bluestone，共同PI）：该项目的主要目标是：（1）阐明参与诱导和维持调节性T细胞（Treg）的信号;（2）了解Treg控制潜在致病效应细胞的机制。 项目2 -SLE中靶向抗原特异性T细胞（大卫戴克，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疗效的基础;和（2）开发新的抗原特异性方法来治疗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）：该核心设施将提供开发和执行基于细胞和抗体的样品免疫测定的能力（例如，血液、淋巴结等）来自参与ACE试验的患者。将提供的检测包括：流式细胞术; MHC/肽四聚体的产生和染色;通过ELISA、ELISPOT和流式细胞术进行的细胞因子分析; T细胞增殖;和细胞毒性检测。该核心将支持临床中心和项目2。 临床中心，个人项目和免疫监测核心共同组成了一个紧密联系的计划，将新疗法从实验室带到床边，并研究这些疗法延缓自身免疫性疾病的机制。

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.