Asthma Induction by Dendritic Cells and Th2 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。 特应性哮喘是由偏性辅助性T细胞2（Th 2）对过敏原的反应引起的。 在小鼠模型中，用银脉冲树突状细胞内致敏并用银激发的小鼠出现气道高反应性、肺嗜酸性粒细胞增多和炎症。 肺具有更偏向Th 2的环境，并且在Ag激发的小鼠中，致敏的T细胞似乎在肺中比淋巴结分裂得更快，尽管淋巴结被认为是T细胞活化和发育的部位。 在这项研究中，发现肺DC由多个亚群组成。 对DC迁移的研究表明，次级淋巴细胞趋化因子（SLC/CCL 21）可能是DC向引流LN迁移的关键趋化因子。 在肺免疫小鼠的肺而不是淋巴结中，存在大量产生干扰素-γ的CD 8 + T细胞（Tc 1），导致肺中更多的Th 2-基础环境。 这些结果支持以下假设：“在肺中呈递抗原并介导Th 2偏向性应答的DC亚群发生在肺中。 对于T淋巴细胞和DC迁移至淋巴结，SLC是主要介导者。 由于Th 1和Tc 1细胞数量在炎症性肺中非常低，活化的T细胞很容易发育成Th 2细胞。“在这个提议中，实验的目的是支持这一假设。 其目标包括：（1）肺中DC亚群的分离和功能研究;（2）作为肺DC和T细胞迁移至淋巴结的关键趋化因子受体/趋化因子相互作用的CCR 7/SLC相互作用的研究。 其他重要的候选趋化因子受体如CCR 2在介导DC迁移中的作用也将被检查;和（3）在哮喘发病过程中产生IFN-γ的CD 8 + T细胞从肺中迁移的研究。 这些研究将阐明DC和CD 8 + T细胞在哮喘偏性Th 2肺应答中的作用，并为哮喘发病过程中的Th 2偏性应答提供新的机制。 这些结果可能通过干预SLC功能和调节DC、Th 1和产生IFN-γ的CD 8 + T细胞的迁移，为哮喘提供额外的治疗策略。

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.