The pathophysiology of asthma is complex with several pathways capable of mediating airwayhyperresponsiveness (AHR), airway inflammation, and goblet cell metaplasia. Moreover, the contributors tothe initiation/sensitization phase of the disease may differ considerably from the factors responsible for thechallenge/maintenance/progression phase. Because of the difficulties in studying and dissecting thesephases and their underlying pathophysiology in asthmatics, animal models have proven invaluable in thisregard. Despite some limitations, mouse models have provided important insights into the pathophysiologyof (human) asthma, especially when different approaches to allergen exposure have been used to identifyspecific mast cell-lgE-dependent and mast cell-independent pathways which elicit similar phenotypes. Thecentral hypothesis of this project is that a novel and unique subset of CD8+ T cells plays an important role inthe development of altered airway function, lung inflammation, and goblet cell metaplasia, with IL-13 beingthe critical mediator of these responses. We posit that this subset of CD8+ T cells is essential due to theirability to produce IL-13. The key feature in their recruitment (andactivation) in the lung is their expression ofBLT1, a high affinity receptor for leukotriene B4 (LTB4). LTB4 is postulated to be released from activatedmast cells and macrophages in allergen-exposed allergic hosts. Based on extensive preliminary data, wehave placed this unique subset of CD8+BLT1+IL-13+ T cells at the core of allergic responses in the lung.Using combinations of molecular, cellular, and biologic tools we will define the distribution and regulation ofBLT1 expression on immune/inflammatory cells in the allergic lung, the consequences of LTB4 ligation ofBLT1, the specific role of BLT1on T cell subsets, and their interactions in the development of AHR and lunginflammation as well as identifying the sources of LTB4 in allergen-exposed mice. In the last specific aim,we will translate these findings in allergic mice to clinical studies of asthmatics, defining the role of thisunique, pathogenic subset of CD8+BLT1+IL-13+ T cells, which we demonstrated in BAL and lung tissue,determining whether they are increased in numbers in corticosteroid-resistant asthmatics and whetherinhibition of LTB4 production leads to lower numbers of these cells in the airways and improved lung functionin this subset of asthmatics. This project will provide novel insights into the pathogenesis and heterogeneityof asthma and provides a critical link to the two other projects in this program grant.
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