Role of L2pB1 Cells on Central Immune Tolerance in Systemic Lupus Erythematosus

L2pB1 细胞对系统性红斑狼疮中枢免疫耐受的作用

• 批准号: 7980525
• 负责人: Xuemei Zhong
• 金额: $ 8.45万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-08-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7980525
• 关键词: Adoptive Transfer; Affect; Animal Model; Antibodies; Antigen Presentation; Antigen-Presenting Cells; Antigens; Apoptosis; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Biological Assay; Cells; Cellular biology; Clinical; Clinical Research; Clinical Trials; Complex; Data; Development; Diffusion; Disease; Environment; Event; Feedback; Future; Generations; Grant; Hand; Hassall' s Corpuscle; Human; Immune; Immune Tolerance; Immune system; Immunology; Immunotherapy; In Vitro; Infiltration; Inflammatory; Investigation; Kinetics; Knowledge; Lupus; MS4A1 gene; Mediating; Modeling; Monoclonal Antibody CD20; Mus; Nature; Organ failure; Patients; Peritoneal; Phase; Production; Recovery; Regulation; Regulatory T-Lymphocyte; Reporting; Role; Societies; Solutions; Staging; Structure; Structure of thymic medulla; Symptoms; Systemic Lupus Erythematosus; T cell differentiation; T-Cell Development; T-Lymphocyte; Therapeutic; Therapeutic Intervention; Thymic epithelial cell; Thymus Gland; arm; base; body system; cell motility; central tolerance; chemokine; chemokine receptor; clinical efficacy; cost; design; humanized antibody; improved; in vivo; male; migration; novel; peripheral blood; prevent; public health relevance; rituximab; socioeconomics

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE) is a complex autoimmune disease with no effective cure. The major clinical manifestation of SLE is the production of a variety of autoantibodies affecting multiple organ systems. Although almost all immune components could be involved at different stages of SLE development, antibody-producing B cells have been the focus of blame. Several therapeutic interventions aimed to deplete B cells have been under clinical trials. Recently, the phase II/III clinical trial of Rituximab, a depleting anti-CD20 monoclonal antibody, failed to demonstrate clinical efficacy in treating SLE patients. Together with other controversial B cell- depleting trials, a better understanding of B cell immunology in SLE is urgently needed for future therapeutics design. Studies have shown that B cells are not always pathogenic in autoimmune diseases. In some animal models, depleting B cells not only failed to alleviate symptoms, but also prevented prompt recovery from diseases. Others have reported that B cells can even suppress autoimmunity through various mechanisms. However, the true identity of such "suppressive" or regulatory B cells is still elusive. Our preliminary data suggested that B1 B cells have previously unknown regulatory functions. Moreover, we found a new subpopulation of B1 B cells that is highly auto-reactive with promiscuity in recognition SLE related autoantigens and can be detected in both murine lupus and human autoimmune patients. In the murine lupus model, we have shown that this B cell subset is elevated in the peripheral blood and most importantly infiltrates into the thymus. Based on our preliminary results, we hypothesize that in SLE the increase of B1 cells in the thymus may reflect a feedback effort of the immune system to reinforce central tolerance, which might be breached by the overwhelming inflammatory environment that counters the regulatory functions of B1 B cells. In this RO3 grant, we propose to obtain preliminary data on the in vitro and in vivo regulatory functions of the novel subpopulation of B1 B cells, particularly, its effects on thymic T cell development in healthy and SLE mice. The results of the study will allow us to apply for RO1 grant support for further investigation of the regulatory arm of B cells and how "Breg" themselves are regulated in SLE. PUBLIC HEALTH RELEVANCE: Project narrative Although B cells are thought to contribute to systemic lupus erythematosus (SLE) by producing self-attacking antibodies that leads to multi-organ failure, recent clinical studies suggest that pan-depletion of B cells may not be the optimal solution. We believe that not all B cells are villains in autoimmune diseases, and particularly we suspect a novel subset of B1 B cells could be the "guardian angels" that may be called upon during systemic autoimmune crisis like SLE and can enter the thymus to re-establish central immune tolerance. Our study will provide new knowledge for redesigning future immune therapy for SLE.

描述（申请人提供）：系统性红斑狼疮（SLE）是一种复杂的自身免疫性疾病，目前尚无有效治疗方法。SLE的主要临床表现是产生多种影响多个器官系统的自身抗体。虽然几乎所有的免疫成分都可能参与SLE发展的不同阶段，但产生抗体的B细胞一直是指责的焦点。几种旨在消耗B细胞的治疗干预措施已在临床试验中。近年来，抗CD 20单克隆抗体利妥昔单抗的II/III期临床试验未能证明其治疗SLE患者的临床疗效。与其他有争议的B细胞耗竭试验一起，更好地理解SLE中的B细胞免疫学对于未来的治疗设计是迫切需要的。研究表明，B细胞在自身免疫性疾病中并不总是致病的。在一些动物模型中，耗尽B细胞不仅无法缓解症状，还会阻止疾病的迅速康复。其他人报道说，B细胞甚至可以通过各种机制抑制自身免疫。然而，这种“抑制性”或调节性B细胞的真实身份仍然难以捉摸。我们的初步数据表明，B1 B细胞具有以前未知的调节功能。此外，我们发现了一个新的B1 B细胞亚群，它在识别SLE相关自身抗原时具有高度的自身反应性和混杂性，并且可以在小鼠狼疮和人类自身免疫患者中检测到。在小鼠狼疮模型中，我们已经表明这种B细胞亚群在外周血中升高，最重要的是浸润到胸腺中。基于我们的初步结果，我们假设在SLE中胸腺中B1细胞的增加可能反映了免疫系统加强中枢耐受性的反馈努力，这可能被对抗B1 B细胞调节功能的压倒性炎症环境所破坏。在这RO 3补助金，我们建议获得在体外和体内的新的B1 B细胞亚群的调节功能，特别是在健康和SLE小鼠胸腺T细胞发育的影响的初步数据。这项研究的结果将使我们能够申请RO 1资助，以进一步研究B细胞的调节臂以及“布雷格”本身在SLE中是如何调节的。 公共卫生关系：虽然B细胞被认为通过产生导致多器官衰竭的自我攻击抗体而导致系统性红斑狼疮（SLE），但最近的临床研究表明，B细胞的全耗竭可能不是最佳解决方案。我们相信并非所有的B细胞都是自身免疫性疾病的罪魁祸首，特别是我们怀疑B1 B细胞的一个新的亚群可能是“守护天使”，在系统性自身免疫性危机如SLE期间可能被召唤，并且可以进入胸腺重建中枢免疫耐受。我们的研究将为重新设计未来SLE的免疫治疗提供新的知识。