THe principal goal of the proposed program is the definition of critical immunopathogenetic roles of lipid and peptide mediators in human hypersensitivity states. The molecular and cellular components of abnormal reactions to a variety of environmental and endogenous stimuli will be studied in relation to the mechanisms responsible for excessive production of the mediators and for both functional hyperreactivity of organ systems and unregulated responses of leukocytes and platelets to the mediators. Core laboratories will be established for the performance of reliable standardized assays of leukocyte and platelet function, the purification and quantification of lipid principles in cells and biological fluids, and the determination of the characteristics of cellular receptors for lipid and peptide mediators. Previously developed methods will be adapted in the core laboratories to studies of human immunological diseases and animal models of such diseases. Specific investigations will be directed to the elucidation of the involvement of leukotrienes in hypersensitivity reactions to aspirin, related compounds, and food additives and the participation of leukotrienes and phospholipid mediators in the activation of leukocytes and platelets in adverse responses to radiographic contrast media. The roles of lipid and peptide mediators in the modulation of regulatory subsets of T-lymphocytes will be assessed in relation to seasonal allergies and responses to immunotherapy. The lipid mediators of the vascular reactions in cold urticaria and of the leukocytic components of bullous pemphigoid will be characterized by examining materials collected from patients with elicited attacks or spontaneous episodes of the diseases. The involvement of mast cell-derived mediators in the airway hyperreactivity of natively allergic dogs will be evaluated by analyzing the spectrum of lipid principles generated by canine mastocytoma cells and lung tissue mast cells challenged with IgE-dependent stimuli. The possibilities of endogenous regulation and pharmacological control of the mediators will be assessed in relation to the central mechanisms responsible for each of the allergic, dermatological, and pulmonary hypersensitivity states.
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