Regulatory B10 Cells in Autoimmune Arthritis

自身免疫性关节炎中的调节性 B10 细胞

• 批准号: 7688871
• 负责人: THOMAS F TEDDER
• 金额: $ 77.67万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7688871
• 关键词: Adoptive Transfer; Affect; Affinity; Age; Antibodies; Antigens; Attenuated; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Beta Cell; Blood; CD4 Positive T Lymphocytes; Cell Count; Cell Survival; Cell physiology; Cell surface; Cells; Chronic; Colitis; Collagen Arthritis; Contact hypersensitivity; DBA/1 Mouse; Development; Disease; Equilibrium; Experimental Autoimmune Encephalomyelitis; Generations; Goals; Human; Humoral Immunities; Immune response; In Vitro; Inbred NOD Mice; Individual; Inflammation; Inflammatory Response; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Knowledge; Lymphoid Tissue; Mediator of activation protein; Methods; Modeling; Mus; Pathogenesis; Patients; Phenotype; Population; Pre-Clinical Model; Production; Property; Regulation; Research Proposals; Resolution; Rheumatoid Arthritis; Role; Specificity; Spleen; Stimulus; Symptoms; Syndrome; Systemic Lupus Erythematosus; T-Cell Activation; T-Lymphocyte Subsets; Testing; Therapeutic; Therapeutic Intervention; Therapeutic Uses; Time; Tissues; Wild Type Mouse; autoimmune arthritis; autoreactive B cell; cytokine; in vitro Assay; in vivo; migration; mouse model; pre-clinical; receptor; response; rituximab

B lymphocytes are central mediators of humoral immunity. Aberrant B cell function also contributes to multiple autoimmune diseases, including rheumatoid arthritis (RA). In addition, we and others have recently found that B cells also serve critical negative regulatory functions during adaptive CD4+ T cell responses that can dampen both cellular and humoral immune responses, and the development of autoimmunity. This unexpected observation is explained in part by the identification of a potent regulatory B cell subset that dramatically attenuates Th1 immune responses and autoimmunity in mice. This regulatory B cell subset is uniquely CD1d+CD5+, produces IL-10. and represents 1-2% of total spleen B cells in wild type mice and <1% of circulating human B cells. We call this subset B10 cells to emphasize that they are the predominant, if not exclusive, B cell population that produces IL-10 and to distinguish them from other regulatory subsets that may also exist. B10 cell numbers within tissues increase significantly in mice with autoimmunity and age. In this proposal, we hypothesize that antigen-specific regulatory B10 cells influence autoimmune disease in both mice and humans. We will test this hypothesis and examine B10 cell generation, function, and mechanisms of action using the mouse collagen-induced arthritis (CIA) model of RA and B cells from patients with RA. In four specific aims, the proposed studies will identify the extent that the B10 subset modulates immune responses during autoimmunity, determine whether B10 cells can be manipulated for therapeutic benefit, and identify and characterize this unique B cell subset in normal humans and patients with autoimmunity. Specific Aim 1 will identify and characterize the B10 cell subset before, during and after CIA induction; Specific Aim 2 will characterize B10 cell function during CIA; Specific Aim 3 will develop an in vivo preclinical mouse model for B10 cell adoptive therapy; and Specific Aim 4 will identify and characterize the B10 subset during human autoimmune disease. These overlapping studies will significantly expand our knowledge of how B10 cells regulate both normal and abnormal immune responses in both species.

B淋巴细胞是体液免疫的核心介质。 B 细胞功能异常也会导致 多种自身免疫性疾病，包括类风湿性关节炎（RA）。此外，我们和其他人还 最近发现 B 细胞在适应性 CD4+ T 细胞过程中也发挥关键的负调节功能 可以抑制细胞和体液免疫反应的反应，以及 自身免疫。这一意外的观察结果可以部分地通过识别出一种有效的物质来解释。 调节性 B 细胞亚群，可显着减弱 Th1 免疫反应和自身免疫 老鼠。该调节性 B 细胞亚群是独特的 CD1d+CD5+，产生 IL-10。并代表 1-2% 野生型小鼠的脾脏 B 细胞总数和循环人类 B 细胞的 1%。我们称这个子集为 B10 细胞以强调它们是产生 IL-10 的主要（如果不是唯一的）B 细胞群 并将它们与其他可能存在的监管子集区分开来。内B10细胞数 具有自身免疫性和年龄的小鼠的组织显着增加。在这个提案中，我们假设 抗原特异性调节 B10 细胞影响小鼠和人类的自身免疫性疾病。我们 将测试这一假设并使用以下方法检查 B10 细胞的生成、功能和作用机制： RA小鼠胶原诱导关节炎（CIA）模型和来自RA患者的B细胞。在四 为了实现特定目标，拟议的研究将确定 B10 子集调节免疫的程度 自身免疫期间的反应，确定是否可以操纵 B10 细胞进行治疗 受益，并识别和表征正常人和患者中这种独特的 B 细胞亚群 自身免疫。具体目标 1 将在之前、期间和之后识别和表征 B10 细胞亚群 中央情报局入职；具体目标 2 将表征 CIA 期间 B10 细胞的功能；具体目标 3 将制定 用于 B10 细胞过继治疗的体内临床前小鼠模型；具体目标 4 将确定并 描述人类自身免疫性疾病期间 B10 子集的特征。这些重叠的研究将 显着扩展了我们对 B10 细胞如何调节正常和异常免疫的了解 两个物种的反应。