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.
