The central focus of this collaborative and synergistic program directed to the effector pathways of allergic inflammation continues to be on the mast and the cysteinyl leukotriene- generating pathway in certain hematopoietic cell types utilizing physiologic, cellular, and molecular assessments. The ongoing approach is broadened by a shift from the mouse to the human for studies in vitro of the cytokine regulation of mast cells and of the regulatory membrane proteins homologous to mouse gp49 and by analyses of effector responses in mice with select gene disruptions (alphaEbeta7 and LTC4 synthase). The development of human mast cells from cord blood progenitors with stem cell factor (SCF), interleukin 6 (IL-6), and IL-10 has allowed recognition of a range of functional receptors for cytokines (IL- 3R, GM-CSFR) and adhesion ligands. As a result, analysis can proceed of the effects of Th2 cell-type cytokines, IL-3, GM-CSF, and IL-9, on human mast cell proliferation, apoptosis, protease phenotype, and expression of the cysteinyl leukotriene-and PGD2- generating pathways. The cloning of the human homologues, designated leukocyte immunoglobulin-like receptors (LIRs), of mouse gp49B1, which signals to attenuate FcepsilonRI activation of mouse mast cells, permits study of their counterregulatory function for human effector cells such as mast cells and eosinophils. The cloning of the cDNA and genes for human and mouse LTC4 synthase, the integral perinuclear membrane protein pivotal to the biosythesis of the parent, LTC4, of the receptor- active cysteinyl leukotrienes implicated in bronchial asthma, provides the opportunity to generate mice with a transgene and with a disrupted gene so as to isolate the effects of excessive of absent cysteinyl leukotriene generation on most inflammatory responses from the effects of proximal pathway gene disruptions. The generation of mice with alphaEbeta7 gene disruption and the evidence of anomalous T cell function provides an opportunity to relate reactive mast cell hyperplasia and tissue eosinophil infiltration in situ to regional cell responses in lung with protein sensitization and challenge and in jejunum with Trichinella spiralis infection, respectively. Taken together, these studies will provide new information on the regulated expression of human genes or effector proteins in mast cells, on the distribution and counterregulatory function of LIRs for cells central to allergic inflammation, on the relationship between an integrin and T cell-determined mast cell distribution/function, and on in situ effects of the cysteinyl leukotrienes in mice.
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