Asthma Induction by Dendritic Cells and Th2 Cells

描述(申请人提供)：哮喘是一种重要的疾病，占总人口的5%。特应性哮喘是由偏向的辅助性T细胞2(Th2)对变应原的反应引起的。在小鼠模型中，经气管内注入抗原冲击的树突状细胞并用抗原攻击的小鼠出现呼吸道高反应性、肺嗜酸性粒细胞增多和炎症。肺部有一个更偏向Th2的环境，在Ag挑战的小鼠中，准备好的T细胞在肺部似乎比淋巴结分裂得更快，尽管淋巴被认为是T细胞激活和发育的场所。本研究发现肺树突状细胞由多个亚群组成。对DC迁移的研究表明，次级淋巴趋化因子(SLC/CCL21)可能是DC向引流性LN迁移的关键趋化因子。在肺免疫的小鼠的肺中，而不是在淋巴结中，存在大量产生干扰素-伽马的CD8+T细胞(Tc1)，导致肺内更多地以Th2为基础的环境。这些结果支持这样一种假设：“肺中存在一个DC亚群，它呈递抗原并介导以Th2为主的反应。对于T淋巴细胞和DC向淋巴结的迁移，SLC是一个主要的介导者。因为Th1和Tc1细胞在炎症肺中数量很少，激活的T细胞很容易发展成Th2细胞。”在这项提议中，实验旨在支持这一假设。目的包括：(1)肺内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/趋化因子相互作用的研究。还将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；以及(3)在哮喘发病过程中产生干扰素-伽马的CD8+T细胞从肺外迁移的研究。这些研究将阐明DC和CD8+T细胞在哮喘偏向Th2肺反应中的作用，并为哮喘发病机制中偏向Th2反应提供新的机制。这一结果可能通过干扰SLC功能和通过调节DC、Th1和产生干扰素-γ的CD8+T细胞的迁移来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.