The overall goal of this proposal is to acquire an enhanced understanding of the inflammatory processes that underlie the asthmatic diathesis. This will be accomplished by investigating the contribution that T cells and cytokines make to histologic, immunologic and physiologic features of this disorder. Underlying this application are 2 important hypotheses. They are that: (1) The inflammatory responses underlying classic antigen (allergen)-, hapten- and virus-induced asthma are similar at some levels and different in others. (2) Asthmatic inflammation is complex and contains components that induce, do not alter and diminish airways hyperresponsiveness (AHR) and bronchospasm. Six projects in this Center will focus on these issues. They are: (1) Interleukin-11 in Viral Asthma. These studies will define the role that IL-11 plays in viral asthma and compare these findings to classic antigen-and hapten-induced airways inflammation and hyperresponsiveness; (2) Regulation of Th2 Effector Function in the Airway. This project will directly explore the relationship between Th1 and Th2 mediated airways inflammation and AHR and investigate T cell-mediated and cytokine-based strategies for regulating Th2 effector function; (3) Molecular Analysis of IL-5 Gene Transcription. This project will characterize the key response elements in the IL-5 promoter that regulate IL-5 gene transcription in vitro and in vivo and compare the transcriptional regulation in Th1 and Th2 T cells; (4) Transgenic Modeling of Airway Inflammation in Asthma. This project will characterize the effector functions of eosinophil regulating and derived cytokines when overexpressed in a lung airway specific/selective fashion and compare the response of these animals to antigen, hapten and virus; (5) Cytokines and Adhesion Molecules in Hapten-Induced AHR. This project will characterize the inflammatory process in the airway of hapten sensitized and challenged animals, correlate this inflammatory process with microvascular endothelial adhesion molecule expression and investigate the relationship between adhesion molecule expression, tissue infiltration and AHR; (6) T Cells in the Pathogenesis of Human Isocyanate Asthma. This study will characterize the T cell abnormalities and inflammatory response in human isocyanate asthma, investigate hapten-specific T lymphocyte responses to isocyanates in vitro and identify peripheral blood markers of early disease or host susceptibility. The SCOR also includes a Clinical and Data Management Core, a Pathology and Morphology Core, a Transgenic Mouse Core, a Mouse Physiology Core, and An administrative Core. Interactions between the projects and Core facilities and amongst the investigators will lead to exciting new information regarding the inflammatory pathogenesis of the asthmatic diathesis.
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