Mechanisms of B Cell Responses in Autoimmune Disease

自身免疫性疾病中 B 细胞反应的机制

• 批准号: 7809548
• 负责人: Eugene William St. Clair
• 金额: $ 636.16万
• 依托单位: DUKE UNIVERSITY
• 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 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7809548
• 关键词: Mechanisms; Cell; Responses; Autoimmune; Disease

DESCRIPTION (provided by applicant): This application is a competitive renewal of the Autoimmunity Center of Excellence (ACE) at Duke. Its research focus will continue to be modulation of B cell responses in autoimmune disease. The ACE will be under the leadership of Dr. E. William St. Clair, Professor of Medicine and Immunology. For the past 5 years, Duke has been a productive member of the ACE network, contributing new insights into the developmental pathways of B cells and the mechanisms of B cell directed therapy. The proposed ACE builds on these discoveries and will support 2 new basic science projects, 5 ongoing and 2 new clinical trials, and an Administrative Core, and continue to emphasize a strong and fluid integration between the bench and the bedside. Tedder and colleagues have recently found that a phenotypically unqiue subset of B cells secreting IL-10 (called B10 cells) serve as critical negative regulators during adaptive CD4+ T cells responses, and dramatically suppress Th1 immune responses and autoimmune disease in mice. For Basic Research Project 1, they will examine the hypothesis that antigen-specific regulatory B10 cells modulate autoimmune responses in mice and man and that they can be manipulated for therapeutic gain. A picture is gradually emerging about the precursors of self-reactive B cells in autoimmune disease. Kelsoe and coworkers in Basic Research Project 2 will investigate developmentally regulated expression of activated cytidine deaminase (AID) in human fetal and neonatal pre-, pro, and immature/transitional B cells and its relationship to the generation of self-reactive B cells in human autoimmune disease, potentially eludidating another pathway of B cell self-reactivity outside the confines of normal tolerance mechanisms. We propose two new clinical trials to investigate lymphotoxin-beta receptor fusion protein as a treatment for primary Sj"gren's syndrome, and rituximab therapy for bullous pemphigoid. A Pilot Research Project is also proposed to engineer tetramers of self-antigen enabling the identification and characterization of self-reactive B cells, which will have implications for the goals of the clinical and other basic research projects. Overall, the Duke ACE will bridge these basic and clinical studies to advance our understanding of autoimmune disease. The B cell is a type of immune cell essential to autoimmunity. The goal of the proposed Autoimmunity Center of Excellence at Duke is to improve our understanding of the roles played by B cells in human autoimmune disease. The projects are designed to be highly integrative between the bench and the bedside, with collaborations between basic and clinical scientists. These studies may lead to better treatments. CLINICAL COMPONENT: Clinical Component (ST CLAIR, W) CLINICAL COMPONENT DESCRIPTION (provided by applicant): The Clinical Research Component of the Autoimmunity Center of Excellence shares with the Basic Research omponent an overall goal of advancing our understanding about the role of B cells in the pathogenesis of autoimmune diseases. This component will be directed by Dr. E. William St. Clair. During the past 5 years, the Duke ACE has brought 3 new clinical trial concepts to the ACE Steering Committee, resulting in 1 completed trial, 1 ongoing trial, and 1 protocol in development. We are also participating in 3 other ongoing ACE-sponsored clinical trials. Therefore, substantial clinical research activity will carry over to the next funding cycle. Our center is organized to support clinical trials in rheumatology, dermatology, gastroenterology, hematology, and neurology. We have access to several large patient populations, including patiens with rheumatoid arthritis, systemic lupus erythematosus, primary Sj"gren's syndrome, scleroderma, autoimmune blistering disease, psoriasis, inflammatory bowel disease, autoimmune hepatitis, anti-phospholipid antibody syndrome, and myasthenia gravis. Each of these disease areas has leadership from one or more physician-investigators with significant clinical trial experience, including an example of a productive inter-institutional collaboration. The physician leadership is supported by an ample infrastructure that provides clinical research space, infusion facilities, experienced clinical coordinators, and an Immune Monitoring Component. The Clinical Research Component aligns with the ACE at a thematic level, with substantial collaborations between basic and clinical scientists. To this end, the proposed clinical trial concepts will focus on B cell directed therapy. In one case, we propose to examine the clinical efficacy of lymphtoxin-beta receptor fusion protein in the treatment of primary Sj"gren's syndrome, and have already secured commitment from the industry sponsor to provide study drug for this trial. The other application will investigate rituximab as initial therapy for bullous pemphigoid. The mechanistic studies for these proposed trials as well as current trials are highly integrated with the basic research projects. The Clinical Research Component will make a significant contribution to the ACE enterprise during the upcoming funding cycle. The Clinical Research Component will support clinical trials sponsored by the Autoimmunity Centers of Excellence in several disease areas, including rheumatology, dermatology, gastroenterology, hematology, and neurology. It has been productive during the current funding cycle, and has the capability, as shown in this application, to generate new ideas for clinical trials that can be translated into well-designed studies.

描述(由申请人提供)：此申请是杜克大学自动免疫卓越中心(ACE)的竞争性续签。它的研究重点将继续是自身免疫性疾病中B细胞反应的调节。ACE将由医学和免疫学教授E.William St.Clair博士领导。在过去的5年里，杜克一直是ACE网络中富有成效的成员，为B细胞的发育途径和B细胞定向治疗的机制提供了新的见解。拟议的ACE建立在这些发现的基础上，将支持2个新的基础科学项目、5个正在进行的临床试验和2个新的临床试验，以及一个管理核心，并继续强调工作台和床边之间的强大和流畅的整合。Tedder和他的同事最近发现，分泌IL-10的一组表型独特的B细胞(称为B10细胞)在适应性CD4+T细胞反应中充当关键的负调节因子，并显著抑制Th1免疫反应和小鼠的自身免疫性疾病。在基础研究项目1中，他们将检验这样一个假设，即抗原特异性调节B10细胞调节小鼠和人类的自身免疫反应，并且它们可以被操纵以获得治疗收益。一幅关于自身免疫性疾病中自身反应性B细胞前体的图景正在逐渐浮现。Kelsoe和他的同事在基础研究项目2中将研究激活的胞苷脱氨酶(AID)在人类胚胎和新生儿前、前和未成熟/过渡性B细胞中的发育调节表达及其与人类自身免疫疾病中自我反应性B细胞的产生的关系，潜在地掩盖了B细胞自我反应性的另一种途径，超出了正常耐受机制的范围。我们提出了两个新的临床试验，以研究淋巴毒素-β受体融合蛋白作为治疗原发干燥综合征的方法，以及利妥昔单抗治疗大疱性类天疱疮。我们还提出了一个试点研究项目，以设计能够识别和表征自我反应性B细胞的自我抗原四聚体，这将对临床和其他基础研究项目的目标产生影响。总体而言，杜克大学ACE将在这些基础和临床研究之间架起桥梁，促进我们对自身免疫性疾病的理解。 B细胞是一种对自身免疫至关重要的免疫细胞。杜克大学拟议的自身免疫卓越中心的目标是提高我们对B细胞在人类自身免疫性疾病中所起作用的理解。这些项目被设计为在长凳和床边之间高度整合，基础科学家和临床科学家之间的合作。这些研究可能会带来更好的治疗方法。 临床部分：临床部分(圣克莱尔，W) 临床部分描述(由申请人提供)：自身免疫卓越中心的临床研究部分与基础研究部分共享一个总体目标，即促进我们对B细胞在自身免疫性疾病发病机制中的作用的理解。这一部分将由E·威廉·圣克莱尔博士指导。在过去的5年里，Duke ACE向ACE指导委员会带来了3个新的临床试验概念，导致1个已完成的试验、1个正在进行的试验和1个正在开发的方案。我们还参与了另外3项由ACE赞助的临床试验。因此，大量的临床研究活动将延续到下一个资助周期。我们的中心旨在支持风湿科、皮肤科、胃肠科、血液科和神经科的临床试验。我们可以接触到几个大的患者群体，包括类风湿性关节炎、系统性红斑狼疮、原发性干燥综合征、硬皮病、自身免疫性水泡病、牛皮癣、炎症性肠病、自身免疫性肝炎、抗磷脂抗体综合征和重症肌无力。这些疾病领域中的每一个都有一名或多名具有重要临床试验经验的医生-研究人员的领导，包括一个富有成效的机构间合作的例子。医生的领导力得到了充足的基础设施的支持，该基础设施提供了临床研究空间、输液设施、经验丰富的临床协调员和免疫监测组件。临床研究部分在主题层面上与ACE保持一致，基础和临床科学家之间进行了实质性的合作。为此，拟议的临床试验概念将集中在B细胞定向治疗上。在一个案例中，我们建议检查淋巴毒素-β受体融合蛋白在治疗原发性干燥综合征中的临床疗效，并已获得行业赞助商的承诺，为该试验提供研究药物。另一项应用将研究利妥昔单抗作为大疱性类天疱疮的初始治疗方法。这些拟议试验以及目前试验的机制研究与基础研究项目高度结合。在即将到来的资金周期中，临床研究部门将为ACE企业做出重大贡献。 临床研究部分将支持由自身免疫卓越中心赞助的几个疾病领域的临床试验，包括风湿科、皮肤科、胃肠科、血液科和神经科。它在当前的资金周期中一直是富有成效的，并有能力产生可转化为精心设计的研究的临床试验的新想法，如本申请所示。