CELLULAR BASIS OF HYPERSENSITIVITY DISEASES

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The central theme of this ongoing study of allergic inflammation involves the cytokine-regulated development of mast cells, eosinophils, and the 5-lipoxygenase/leukotriene (LT)C4 synthase pathway. The importance of the cysteinyl leukotrienes to bronchial asthma is supported by the evidence of their over-production and by the clinical benefit derived from agents that attenuate their production or action. An ongoing project focused upon asthma morbidity among inner-city minorities will shift its emphasis from the clinical benefits of educating both patients and their physicians about asthma to achieving increased participation by the patient population at risk. The development of systemic mastocytosis in the mouse by adoptive transfer of immortalized V3 mast cells allows in vivo demonstration of the tissue-directed differentiation and maturation of monocytoid progenitors, permits studies of secretory granule processing in situ, and presents a model in which organ-related fibrosis can be analyzed. The expression cloning of the cDNA for human LTC4 synthase, along with the development of LTC4 synthase-specific antibody, allows definition of cellular and subcellular distribution by immunodetection and function by kinetic studies of mutated protein. The development of mononuclear eosinophils from cord blood and of segmented/hypersegmented functionally-primed eosinophils from normal eosinophils by different culture systems provides the opportunity to compare the biochemical characteristics of two phenotypes observed among the hypodense, disease-associated eosinophil populations. In addition, the developmental sequence for the components of the cysteinyl leukotriene-generating pathway can be defined during eosinophilopoiesis from cord blood by molecular, protein, and functional analyses. Finally, the cloning of the cDNAs and genes for the gp49 family of proteins of the immunoglobulin superfamily that are preferentially expressed by mouse mast cells and macrophages has led to the definition of the gp49 family and the observation that its members mediate cell-cell interactions with activated T cells. This finding, and the isolation of a related cDNA from adherent human monocyte/ macrophages, allows an analysis of the adhesion function of gp49 family members in two species, their cell profile of expression, and the search for the counter ligands by cell/cell and solid phase assays with transfectants and recombinant proteins, respectively.