Asthma Induction by Dendritic Cells and Th2 Cells

树突状细胞和 Th2 细胞诱导哮喘

• 批准号: 6841211
• 负责人: Sun-Sang Joseph Sung
• 金额: $ 34.31万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-01-01 至 2007-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6841211
• 关键词: allergens; antigens; asthma; cell migration; cellular immunity; chemokine; chemokine receptor; cytotoxic T lymphocyte; dendritic cells; enzyme linked immunosorbent assay; flow cytometry; genetically modified animals; helper T lymphocyte; inflammation; interferon gamma; laboratory mouse; lung; lymph nodes; polymerase chain reaction

DESCRIPTION (provided by applicant): Asthma is an important disease that afflicts 5% of the general population. Atopic asthma is caused by biased-T helper 2 (Th2) responses to allergens. In a mouse model, mice primed intratracheally with Ag-pulsed dendritic cells and challenged with Ag developed airway hyperresponsiveness, and lung eosinophilia and inflammation. Lungs have a more Th2-biased environment and primed T cells seem to divide faster in the lungs than lymph nodes in Ag-challenged mice, although the lymph node is believed to be the site of T cell activation and development. In this study, lung DC have been found to be composed of multiple subset. Studies on DC migration suggest that secondary lymphoid chemokine (SLC/CCL21) may be a key chemokine for DC migration to draining LN. In the lung but not lymph nodes of lung-immunized mice, large numbers of interferon-gamma-producing CD8+ T cells (Tc1) were present, resulting in a more Th2-baised environment in the lungs. These results support the hypothesis that: "a DC subset that presents antigen in lungs and mediates a Th2-biased response occurs in lungs. For T lymphocyte and DC migration to lymph nodes, SLC is a major mediator. Because Th1 and Tc1 cell numbers are very low in the inflammatory lungs, activated T cells readily develop into Th2 cells." In this proposal, experiments are designed to support this hypothesis. The aims consist of: (1) the isolation and functional studies of DC subsets in lungs; (2) the studies of CCR7/SLC interaction as a key chemokine receptor/chemokine interaction for lung DC and T cell migration to lymph nodes. The roles of other important candidate chemokine receptors such as CCR2 in mediating DC migration will also be examined; and (3) the studies of the migration of IFN-gamma-producing CD8+ T cells away from lungs during asthma pathogenesis. These studies will clarify the roles of DC and CD8+ T cells in the biased-Th2 lung response in asthma and provide a novel mechanism for Th2-biased responses during asthma pathogenesis. The results may provide additional therapeutic strategies in asthma by the interference of SLC functions and by regulating the migration of DC, Th1, and IFN-gamma-producing CD8+ T cells.

描述（由申请人提供）：哮喘是一种重要的疾病，困扰着5%的普通人群。特应性哮喘是由偏倚t辅助2 （Th2）对过敏原的反应引起的。在小鼠模型中，小鼠气管内注入银脉冲树突状细胞并受到银刺激后，出现气道高反应性、肺嗜酸性粒细胞增多和炎症。肺部有一个更偏向于th2的环境，在ag挑战小鼠中，启动T细胞似乎比淋巴结分裂得更快，尽管淋巴结被认为是T细胞激活和发育的地方。本研究发现肺DC由多个亚群组成。有关DC迁移的研究表明，次级淋巴样趋化因子（SLC/CCL21）可能是DC迁移至引流LN的关键趋化因子。在肺免疫小鼠的肺部而不是淋巴结中，存在大量产生干扰素- γ的CD8+ T细胞（Tc1），导致肺部更以th2为基础的环境。这些结果支持以下假设：“DC亚群在肺中呈现抗原并介导th2偏倚反应发生在肺中。对于T淋巴细胞和DC向淋巴结的迁移，SLC是一个主要的中介。因为炎性肺中Th1和Tc1细胞数量非常低，激活的T细胞很容易发育成Th2细胞。”在这个提议中，实验被设计来支持这个假设。目的包括：(1)肺中DC亚群的分离和功能研究；(2) CCR7/SLC相互作用作为肺DC和T细胞向淋巴结迁移的关键趋化因子受体/趋化因子相互作用研究。其他重要的候选趋化因子受体如CCR2在介导DC迁移中的作用也将被检查；(3)哮喘发病过程中产生ifn - γ的CD8+ T细胞向肺外迁移的研究。这些研究将阐明DC和CD8+ T细胞在哮喘偏置th2肺反应中的作用，并为哮喘发病过程中th2偏置反应提供新的机制。该结果可能通过干扰SLC功能和调节DC、Th1和产生ifn - γ的CD8+ T细胞的迁移，为哮喘提供额外的治疗策略。