Modulation of B Cell Responses in Autoimmunity

描述(由申请人提供)： 拟建的中心将专注于自身免疫中B细胞反应的调节，并将由风湿病科医学教授E·威廉·圣克莱尔博士领导。它联合了一支杰出和经验丰富的基础和临床研究人员团队。在自身免疫中，B细胞不仅是致病性自身抗体的来源，还可以作为抗原提呈细胞(APC)，通过多种机制刺激病理性炎症反应。B细胞的功能通过B细胞受体复合体以及其他B细胞特异性细胞表面抗原来调节，包括CD20和CD22。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治疗的有吸引力的靶点。此外，我们发现炎性刺激，如肿瘤坏死因子α(TNFpha)，可以促进B细胞从骨髓向外迁移，将大量发育中的B淋巴细胞转移到外周。我们假设异常激活的B细胞是自身免疫临床表达的关键，由此产生的炎症状态为自身反应性B细胞的异常发展和免疫反应的进一步失调提供了环境。提出了两个相互关联的基础研究项目来研究这一假说。免疫学教授兼主席Thomas Tedder博士将领导一个项目，利用他的实验室开发的一组独特的CD20和CD22导向的单抗，研究CD20和CD22在小鼠B细胞功能调节中的作用。另一个项目将由免疫学教授加内特·凯尔索博士领导，并将调查炎症刺激，如肿瘤坏死因子α，对未成熟B细胞的运输和自身反应性B细胞谱系的选择有何影响。由圣克莱尔博士和其他经验丰富的内科科学家领导的临床部分将补充基础研究项目。该小组在类风湿性关节炎(RA)、系统性红斑狼疮、寻常型天疱疮(PV)和其他自身免疫性疾病方面拥有专业知识，并可以接触到许多不同的患者群体进行临床研究。其中一项拟议试验将评估抗CD22单抗治疗类风湿性关节炎的安全性和临床疗效，另一项试验将研究英夫利昔单抗(抗肿瘤坏死因子α)治疗PV。每项试验都包括与基础研究项目目标相结合的机械性研究，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连接基础和临床研究，并应对自身免疫性疾病的免疫治疗产生新的见解。

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.