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: 8466192
• 负责人: Eugene William St. Clair
• 金额: $ 744.22万
• 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 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8466192
• 关键词: Autoimmune Diseases; B-Lymphocytes; response

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.

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）的竞争更新。它的研究重点将继续是对自身免疫性疾病中B细胞反应的调节。 ACE将在医学与免疫学教授E. William St. Clair博士的领导下。在过去的5年中，杜克（Duke）一直是ACE网络的生产成员，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，并将支持两个新的基础科学项目，5个正在进行的和2个新的临床试验以及一个行政核心，并继续强调长凳和床边之间的强大而流畅的整合。 Tedder及其同事最近发现，在自适应CD4+ T细胞反应中，分泌IL-10（称为B10细胞）的B细胞的表型不QIUE子集充当关键的阴性调节剂，并大大抑制小鼠中的Th1免疫反应和自身免疫性疾病。对于基础研究项目1，他们将研究以下假设：抗原特异性的调节性B10细胞调节小鼠和人的自身免疫反应，并且可以通过治疗增益进行操纵。关于自身免疫性疾病中自我反应性B细胞的前体逐渐出现了图片。基础研究项目2中的Kelsoe和同事将研究人类胎儿和新生儿前，Pro和未成熟/过渡/过渡性B细胞中激活的胞苷脱氨酶（AID）的发育调节表达自身免疫性疾病，有可能避免在正常耐受机制的范围之外B细胞自我反应性的另一种途径。我们提出了两项​​新的临床试验，以研究淋巴毒素β受体融合蛋白作为原发性SJ“ Gren's综合征的治疗方法，以及用于大胆pemphigoid的利妥昔单抗治疗。还提出了一个试验性研究项目自我反应性B细胞将对临床和其他基础研究项目的目标产生影响，杜克大学将桥接这些基本和临床研究，以促进我们对自身免疫性疾病的理解。 B细胞是自身免疫必不可少的一种免疫细胞。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发挥的作用的理解。这些项目旨在在基础科学家和临床科学家之间进行合作，在长凳和床边之间具有高度综合性。这些研究可能会导致更好的治疗方法。