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: 8260384
• 负责人: Eugene William St. Clair
• 金额: $ 500.39万
• 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/8260384
• 关键词: Animal Model; Antibodies; Antigens; Antiphospholipid Syndrome; Area; Attention; Autoantigens; Autoimmune Diseases; Autoimmune Hepatitis; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Cell Development; B-Lymphocyte Subsets; B-Lymphocytes; Basic Science; Biological Assay; Biomedical Research; Bulla; Bullous Pemphigoid; CD4 Positive T Lymphocytes; Cells; Cellular Assay; Chimeric Proteins; Clinical; Clinical Research; Clinical Sciences; Clinical Trials; Collaborations; Country; Cytidine Deaminase; Dermatology; Development; Diagnosis; Discipline; Disease; Disease Pathway; Engineering; Environment; Flow Cytometry; Funding; Gastroenterology; Generations; Genomics; Goals; Hematology; Heterogeneity; Human; Immune; Immune response; Immune system; Immunologic Monitoring; Immunology; Incentives; Industry; Inflammation; Inflammatory Bowel Diseases; Infusion procedures; Institution; Interleukin-10; Knowledge; Lead; Leadership; Left; Liquid substance; Logistics; Mediating; Medicine; Mus; Myasthenia Gravis; Neonatal; Neurology; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Physicians; Play; Protocols documentation; Psoriasis; Research; Research Activity; Research Design; Research Infrastructure; Research Personnel; Research Project Grants; Rheumatoid Arthritis; Rheumatology; Role; Safety; Scientific Advances and Accomplishments; Scientist; Scleroderma; Secure; Sjogren' s Syndrome; Syndrome; Systemic Lupus Erythematosus; T cell response; Talents; Technology; Therapeutic; Time; Translating; Work; bench to bedside; clinical efficacy; design; drug discovery; experience; fetal; improved; insight; lymphotoxin beta receptor; man; member; patient population; professor; receptor; research study; response; rituximab; success; therapy development; tool; translational medicine

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）：本申请是杜克自身免疫卓越中心（ACE）的竞争性更新。其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E博士领导。威廉·圣克莱尔，医学和免疫学教授。在过去的5年里，杜克一直是ACE网络的富有成效的成员，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强大而流畅的整合。Tedder及其同事最近发现，分泌IL-10的B细胞（称为B10细胞）的表型独特的亚群在适应性CD 4 + T细胞应答过程中起关键的负调节作用，并显着抑制小鼠的Th 1免疫应答和自身免疫性疾病。对于基础研究项目1，他们将研究抗原特异性调节B10细胞调节小鼠和人类自身免疫反应的假设，并且可以操纵它们以获得治疗效果。关于自身免疫性疾病中自身反应性B细胞的前体的图片逐渐出现。Kelsoe和基础研究项目2的同事将研究人类胎儿和新生儿前、原和未成熟/过渡期B细胞中活化胞苷脱氨酶（AID）的发育调节表达及其与人类自身免疫性疾病中自身反应性B细胞生成的关系，可能揭示正常耐受机制范围外的另一种B细胞自身反应性途径。我们提出了两项新的临床试验，以研究光敏素-β受体融合蛋白作为原发性干燥综合征的治疗方法，以及利妥昔单抗治疗大疱性类天疱疮。还提出了一个试点研究项目，以工程化自身抗原的四聚体，从而能够识别和表征自身反应性B细胞，这将对临床和其他基础研究项目的目标产生影响。总的来说，杜克血管紧张素转换酶将这些基础和临床研究的桥梁，以促进我们对自身免疫性疾病的理解。 B细胞是自身免疫所必需的一种免疫细胞。杜克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。这些项目的设计是高度一体化之间的板凳和床边，与基础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。 临床组件：临床组件（ST CLAIR，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的总体目标相同，即促进我们对B细胞在自身免疫性疾病发病机制中作用的理解。这一部分将由E博士指导。威廉·圣克莱尔在过去5年中，杜克ACE向ACE指导委员会提交了3项新的临床试验概念，其中1项试验已完成，1项试验正在进行，1项方案正在制定中。我们还参与了其他3项正在进行的ACE申办的临床试验。因此，大量的临床研究活动将延续到下一个资助周期。我们的中心组织起来支持风湿病学、皮肤病学、胃肠病学、血液学和神经病学的临床试验。我们接触了几个大的患者群体，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、自身免疫性水疱病、银屑病、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患者。这些疾病领域中的每一个都有一个或多个具有重要临床试验经验的医生-研究者的领导，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，这些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。临床研究部分与ACE在主题层面保持一致，基础和临床科学家之间进行了大量合作。为此，所提出的临床试验概念将集中于B细胞定向治疗。在一个病例中，我们建议检查淋巴毒素-β受体融合蛋白治疗原发性干燥综合征的临床疗效，并已获得行业申办者的承诺，为本试验提供研究药物。另一项申请将研究利妥昔单抗作为大疱性类天疱疮的初始治疗。这些拟议试验以及当前试验的机制研究与基础研究项目高度整合。临床研究部分将在即将到来的资金周期内为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在几个疾病领域赞助的临床试验，包括风湿病学，皮肤病学，胃肠病学，血液学和神经病学。在当前的资助周期中，它是富有成效的，并且有能力，如本申请所示，为临床试验产生新的想法，这些想法可以转化为精心设计的研究。