IMMUNE FUNCTIONS OF ACCESSORY CELLS IN THE LUNG

在这个建议中，我们解决了两个中心问题，在肺树突状细胞 (DC)生物学 1. DC前驱体进入的机制是什么 让肺部接受它们的哨兵功能 2. 扮演什么角色 肉芽肿性炎症中的DC？ 这些问题建立在 根据我们实验室最近的两项观察。 a. DC 前体，而不是他们的成熟同行，进入肺， 使用部分依赖于CD18的机制对趋化因子的应答 整合素和ICAM-1表达。 B. DC是第一个接触 静脉内注射抗原包被的珠粒，从而启动 肉芽肿形成。 DC前体的起源。 I. 我们建立了 表型和功能的DC前体迁移到肺， 证明它们是单核细胞的一个亚群。 二. 差异 在A的敏感性。单核细胞，B.肺间质DC前体 和c.成熟的肺DC对一系列趋化剂的作用在 体外在体内的平行研究检查了如何组织分布的 这些细胞在体内给予趋化剂时发生改变， 气管 三. 通过使用突变小鼠， 抗体，我们将首次证明DC前体 迁移依赖于整合素和免疫球蛋白超家族 粘附分子 在稳定状态下检查原位迁移， 在移民增加的情况下， 用flt3配体处理的循环DC前体的数量。 DC 肉芽肿性炎症的活性。 使用涂有 分枝杆菌抗原，我们诱导肺部肉芽肿， DC群体的表型和抗原呈递活性的时间 在肉芽肿肺门淋巴结和脾脏里 的关键作用 IL-12在肉芽肿性皮肤炎细胞免疫应答中的作用 炎症将通过i. DC中的免疫定位IL-12。 二.通过RT-PCR-ELISA定量IL-12 mRNA和iii. ELISA法测定 对于珠后前12小时内DC的IL-12细胞因子分泌， 接种。 这些研究为我们提供了重要的新见解， 肺DC的生物学，它们在肺的免疫防御中的作用 并提供基本信息， 利用这些细胞来防御吸入的 病原体

In this proposal we address two central questions in lung dendritic cell (DC) biology. 1. What are the mechanisms by which DC precursors enter the lung to adopt their sentinel function? 2. What role is played by DC in granulomatous inflammation? These questions build on the following two observations made recently in our laboratory. a. DC precursors, and not their mature counterparts, enter the lung in response to chemokines using mechanisms that depend, in part, on CD18 integrin and ICAM-1 expression. b. DC are the first cells to contact intravenously injected antigen-coated beads, thereby initiating granuloma formation. Origin of DC precursors. i. We establish the phenotype and function of DC precursors that migrate to the lung and provide evidence that they are a subset of monocytes. ii. Differences in the sensitivity of a. monocytes, b. interstitial lung DC precursors and c. mature lung DC to a series of chemotactic agents is examined in vitro. Parallel studies in vivo examine how the tisssue distribution of these cells is altered when a chemotactic agent is administered intra- tracheally. iii. By using mutant mice treated with blocking antibodies, we will show for the first time that DC precursor transmigration is dependent on integrins and immunoglobulin superfamily adhesion molecules. Transmigration in situ is examined at steady state, under conditions of heightened migration and after generating increased numbers of circulating DC precursors treatment with flt3 ligand. DC activity in granulomatous inflammation. Using beads coated with mycobacterial antigen, we induce granulomas in the lung and examine over time the phenotype and antigen presenting activity of the DC population in the granuloma, hilar lymph nodes and the spleen. The key role of IL-12 in the induction of the cellular immune response in granulomatous inflammation will be demonstrated by i. Immuno-localizing IL-12 in DC. ii. Quantifying IL-12 mRNA by RT-PCR-ELISA and iii. Assaying by ELISA for IL-12 cytokine secretion by DC within the first 12 h after bead inoculation. These studies contribute important new insights into the biology of pulmonary DC, their role in the immune defense of the lung and provide basic information that can be drawn upon to devise strategies to harness these cells in the defense against inhaled pathogens.