IMMUNOREGULATION OF THE CELLS AND MEDIATORS OF ASTHMA

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The goals of this Asthma and Allergic and Immunologic Diseases Cooperative Research Center (AAIDCRC) program at the University of Washington are to define basic pathophysiologic mechanisms of airway inflammation in asthma and determine the critical immunoregulatory signals controlling this inflammatory process. These studies will help design and test new therapeutic interventions to ameliorate or prevent allergic lung injury. Allergen-induced release of 5-lipoxygenase products of arachidonic acid metabolism is important in the pathophysiology of both early-phase and late-phase asthmatic responses. Studies will define how the 5- lipoxygenase pathway is regulated in cells which mediate lung inflammation in asthma and the effects of 5-lipoxygenase inhibition on these inflammatory reactions. The T cell-derived cytokines interleukin-4 (IL-4) and interferon (IFN)-gamma have been implicated in the induction or inhibition, respectively, of the Th2 subset of CD4 T cells, the production of IgE antibodies by B cells, and the growth and attraction to tissues of mast cells and eosinophils. This proposal will address the causal role of these T cell cytokines in producing a pulmonary allergic diathesis by deriving transgenic mice that differ only in their relative capacity to produce IL-4 or IFN-gamma in response to antigenic challenge. The specific influx of eosinophils into the bronchial tissues is a key event in the pathogenesis of late-phase asthmatic responses. Proposed studies will determine the molecular mechanisms by which IL-4 augments the adherence of eosinophils to endothelial cell adhesion molecules and the potential efficacy of antiadhesion treatment in asthma. Asthma morbidity and mortality have greatly increased in the U.S. over the past decade with women and Blacks at particular risk. The Demonstration and Education (D&E) Research Project will examine factors leading to increased asthma mortality in women and minorities in the Pacific Northwest and the U.S. The D&E project and will focus on compliance, education, and psychosocial adjustment issues in teenagers with asthma. A multidisciplinary approach will be employed in these studies. The investigators have a strong history of prior highly productive collaborative research with each other and are expert in the investigative areas of allergy and immunology, cell and molecular biology, physiology, morphology, psychology, medical geography, and biostatistics necessary to address these basic questions on the pathobiology of asthma.