Modulation of B Cell Responses in Autoimmunity

自身免疫中 B 细胞反应的调节

• 批准号: 7226770
• 负责人: Eugene William St. Clair
• 金额: $ 73.23万
• 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 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7226770
• 关键词: Antigen-Presenting Cells; Autoantibodies; Autoimmune Diseases; Autoimmunity; B cell repertoire; B-Lymphocytes; Basic Science; Bone Marrow; CD22 gene; Cell physiology; Clinical; Clinical Investigator; Clinical Research; Clinical Trials; Complement; Complex; Development; Emigrations; Environment; Goals; Head; Immunology; Immunotherapy; Inflammation; Inflammatory; Laboratories; Leadership; MS4A1 gene; Medicine; Monoclonal Antibodies; Monoclonal Antibody Therapy; Mus; Numbers; Pathologic; Patients; Pemphigus Vulgaris; Physicians; Population; Receptors, Antigen, B-Cell; Regulation; Research Project Grants; Rheumatoid Arthritis; Rheumatology; Role; Safety; Scientist; Source; Stimulus; Surface Antigens; Systemic Lupus Erythematosus; Tumor Necrosis Factor-alpha; autoreactive B cell; clinical efficacy; experience; infliximab; insight; professor; response; trafficking

DESCRIPTION (provided by applicant): The proposed Center will focus on the modulation of B cell responses in autoimmunity and will be under the leadership of Dr. E. William St. Clair, Professor of Medicine, Division of Rheumatology. It unites a team of outstanding and experienced basic and clinical investigators. In autoimmunity, B cells not only serve as the source of pathogenic autoantibodies, but they also may function as antigen presenting cells (APCs) and stimulate pathologic inflammation through a variety of mechanisms. B cell function is regulated via the B cell receptor complex as well as other B cell-specific cell surface antigens, including CD20 and CD22. Growing evidence, including our results, indicates CD20 and CD22 are attractive targets for immunotherapy of autoimmune diseases. In addition, we have shown inflammatory stimuli, such as tumor necrosis factor alpha (TNFalpha), can promote the emigration of B cells from the bone marrow, transferring large numbers of developing B lymphocytes to the periphery. We hypothesize aberrantly activated B cells are pivotal to the clinical expression of autoimmunity, and the resulting inflammatory state affords an environment for abnormal development of autoreactive B cells and further dysregulation of the immunological response. Two interrelated basic research projects are proposed to investigate this hypothesis. Dr. Thomas Tedder, Professor and Chair of Immunology, will direct a project examining the roles of CD20 and CD22 in the regulation of B cell function in mouse, taking advantage of a unique panel of CD20 and CD22-directed monoclonal antibodies developed in his laboratory. The other project will be headed by Dr. Garnett Kelsoe, Professor of Immunology, and will investigate to what extent inflammatory stimuli, such as TNFalpha influence the trafficking of immature B cells and selection of the autoreactive B cell repertoire. A clinical component led by Dr. St. Clair and other experienced physician-scientists will complement the basic research projects. This group has expertise in rheumatoid arthritis (RA), systemic lupus erythematosus, pemphigus vulgaris (PV), and other autoimmune diseases as well as access to many different patient populations for clinical studies. One of the proposed trials will evaluate the safety and clinical efficacy of anti-CD22 monoclonal antibody therapy for RA, while the other will investigate infliximab (anti-TNFalpha) therapy for PV. Each of the trials includes mechanistic studies that are integrated with the goals of the basic research projects, providing synergy within the Center. An Administrative Core will oversee the management of these projects. Overall, the Proposed Center will efficiently bridge basic and clinical investigations and should produce new insights into the immunotherapy of autoimmune disease.

描述（由申请人提供）： 拟议的中心将重点介绍自身免疫中B细胞反应的调节，并将在风湿病学系医学教授E. William St. Clair博士的领导下进行。它团结了一支由杰出且经验丰富的基础和临床研究人员组成的团队。在自身免疫性中，B细胞不仅是致病性自身抗体的来源，而且还可以用作抗原呈递细胞（APC），并通过多种机制刺激病理炎症。 B细胞功能通过B细胞受体复合物以及其他B细胞特异性细胞表面抗原（包括CD20和CD22）调节。越来越多的证据，包括我们的结果，表明CD20和CD22是自身免疫性疾病免疫疗法的有吸引力的靶标。此外，我们已经显示出炎性刺激，例如肿瘤坏死因子α（TNFalpha），可以促进B细胞从骨髓中的迁移，从而将大量的B淋巴细胞转移到周围。我们假设异常活化的B细胞对自身免疫性的临床表达至关重要，并且所得的炎症状态为自动反应性B细胞异常发育提供了环境，并进一步失调免疫学反应。提出了两个相互关联的基础研究项目来研究这一假设。免疫学教授兼主席托马斯·泰德（Thomas Tedder）博士将通过利用独特的CD20和CD22指导的单克隆抗体在其实验室中开发的独特的CD20和CD22在B细胞功能中的作用。 另一个项目将由免疫学教授Garnett Kelsoe博士领导，并将在多大程度上调查炎症刺激，例如TNFalpha影响未成熟B细胞的运输和自动反应性B细胞库的选择。由圣克莱尔博士和其他经验丰富的医师科学家领导的临床组成部分将补充基础研究项目。该小组在类风湿关节炎（RA），全身性红斑狼疮，pemphigus ulythigus（PV）和其他自身免疫性疾病方面具有专业知识。拟议的试验之一将评估RA抗CD22单克隆抗体治疗的安全性和临床功效，而另一个将研究Iffriximab（抗TNFALPHA）治疗PV的安全性和临床功效。每个试验都包含与基础研究项目目标相结合的机械研究，从而在中心内提供协同作用。行政核心将监督这些项目的管理。总体而言，拟议的中心将有效地桥接基本和临床研究，并应对自身免疫性疾病的免疫疗法产生新的见解。