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中心介质。异常的B细胞功能也有助于 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CD 4 + T细胞增殖过程中也起着重要的负调节作用， 这些反应可以抑制细胞和体液免疫反应，以及 自身免疫这一意想不到的观察结果部分解释了一种有效的 调节性B细胞亚群，显著减弱Th 1免疫应答和自身免疫， 小鼠这种调节性B细胞亚群是唯一的CD 1d + CD 5+，产生IL-10。占全球人口的1-2% 野生型小鼠的总脾B细胞和<1%的循环人B细胞。我们将此子集称为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 并将它们与可能存在的其他监管子集区分开来。B10细胞数量 在具有自身免疫性和年龄的小鼠中组织显著增加。在本提案中，我们假设， 抗原特异性调节性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，并检查B10细胞的产生，功能和作用机制，使用 小鼠胶原诱导的RA关节炎（CIA）模型和来自RA患者的B细胞。在四 具体目标，拟议的研究将确定B10亚群调节免疫的程度， 在自身免疫过程中的反应，确定是否可以操纵B10细胞用于治疗 受益，并鉴定和表征正常人和患有以下疾病的患者中这种独特的B细胞亚群： 自身免疫具体目标1将在B10细胞亚群的研究之前、期间和之后进行鉴定和表征 CIA诱导;特异性目标2将表征CIA期间B10细胞功能;特异性目标3将开发 用于B10细胞过继治疗的体内临床前小鼠模型;和特定目标4将鉴定和 在人类自身免疫性疾病期间表征B10亚群。这些重叠的研究将 显著扩展了我们对B10细胞如何调节正常和异常免疫的知识 两个物种的反应。