ROLE OF CD40 IN AIRWAY INFLAMMATION

CD40分子与其配体（CD40L）之间的相互作用在体液和细胞介导的免疫反应的发展中起着关键作用。CD40是TNF受体家族的成员；本研究提出的初步数据表明，气道上皮细胞表达CD40。待验证的假设是上皮CD40通过调节介导气道内白细胞迁移和T细胞活化和分化的免疫分子的表达，在肺免疫中起关键作用。在慢性气道炎症反应中，肺可能由于持续的白细胞浸润和随后的炎症介质释放而受损。糖皮质激素是治疗慢性气道炎症最广泛使用的抗炎药物。然而，长期使用这些药物可能导致有害的副作用；因此，需要其他治疗慢性气道炎症的方法。通过免疫分子的表达，气道上皮细胞被认为是调节肺部炎症的重要免疫效应细胞。此外，气道上皮细胞排列在呼吸道的事实表明，这些细胞与迁移到气道管腔的白细胞相互作用。因此，CD40反应性气道上皮细胞和表达CD40L的白细胞（包括活化的T淋巴细胞、嗜酸性粒细胞和肥大细胞）之间的细胞间相互作用可能启动和/或加剧肺免疫反应。上皮细胞CD40在调节免疫应答中的作用将通过以下具体目标来解决：1)检查上皮细胞CD40在肺内白细胞迁移和T细胞活化和分化中的作用；2)描述上皮CD40调节免疫分子表达的信号通路，这些免疫分子介导气道内白细胞迁移和T细胞活化和分化。预计这些研究的新发现将揭示肺免疫的机制，重要的是，可能导致产生靶向气道上皮细胞的治疗药物，以特异性地阻止气道炎症。

Interactions between a molecule CD40 and its ligand (CD40L) play a critical role in the development of humoral and cell-mediated immune responses. CD40 is a member of the TNF receptor family; preliminary data presented in this proposal demonstrate that airway epithelial cells express CD40. The hypothesis to be tested is that epithelial CD40 plays a key role in lung immunity by modulating the expression of immune molecules that mediate leukocyte migration and T cell activation and differentiation within the airway. During a chronic airway inflammatory response, the lung may be damaged as a consequence of persistent leukocyte infiltration and subsequent inflammatory mediator release. Glucocorticoids are the most widely used anti- inflammatory treatment to combat chronic airway inflammation. However, long-term usage of these pharmacologic agents can result in deleterious side-effects; thus, alternative approaches to treating chronic airway inflammation are needed. Through their expression of immune molecules, airway epithelial cells are now considered important immune effector cells that modulate lung inflammation. Moreover, the fact that airway epithelial cells line the respiratory tract suggests that these cells interact with leukocytes that migrate into the lumen of the airway. Therefore, it is likely that cell-cell interactions between CD40- responsive airway epithelial cells and leukocytes that express CD40L, including activated T lymphocytes, eosinophils, and mast cells, initiate and/or exacerbate lung immune responses. The role of epithelial CD40 in modulating immune responses will be addressed through the following specific aims: 1) examine the role of epithelial CD40 in leukocyte migration and T cell activation and differentiation within the lung; and 2) delineate the signaling pathway(s) that epithelial CD40 utilizes to modulate the expression of immune molecules that mediate leukocyte migration and T cell activation and differentiation within the airway. It is anticipated that novel findings derived from these studies will shed light on the mechanisms of lung immunity and, importantly, may lead to the generation of therapeutic agents that target airway epithelial cells specifically to arrest airway inflammation.