The overall goal of this proposal is to understand how CD4 T lymphocytes and their associated cytokines regulate the chronic inflammatory disorder which is characteristic of asthma. Asthma airway inflammation involves eosinophils, lymphocytes and mast cells, all of which release chemical mediators in the local lung environment which are thought to cause the observed airway responses. There is considerable evidence that Th2 CD4 effector cells are associated with chronic airway inflammation. In this application, the direct role of Th2 cells and their associated cytokines in the induction of lung inflammatory responses to airway hyperresponsiveness will be tested. Underlying the proposal are 2 hypotheses: First, IL-4, or int he absence of IL-4, IL-13 production by Th2 cells, and subsequent Stat6 signaling by lung endothelial cells are required for Th2 recruitment to the lung. Eosinophil recruitment depends on the presence of Th2 cells and the production of the Th2 cell associated cytokines, IL-4 and IL-5. Second, the appearance of eosinophils in the airway is IL-4 dependent in that in the absence of IL-4, eosinophils in the lung parenchyma do not migrate into the airway. The association of airway eosinophilia with airway responsiveness will be tested. These hypothesis will be tested in 3 Specific Aims: 1) To determine the role of IL-13 and Th2 cell recruitment to the lung; 2) to determine the mechanism by which Th2 derived IL-4 regulates lung and airway eosinophilia; and 3) to determine the cellular molecular and genetic factors that regulate airway eosinophilia following epicutaneous immunization. Using a newly established mouse model in which the Th2 cells and local lung environment can be independently genetically manipulated, the precise function of factors important in the induction of inflammation will be determined.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Biology and Pathology Study Section (LBPA)
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Yale University
Schools of Medicine
New Haven
United States
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