Eosinophils are a distinct class of relatively long-lived and predominantly tissue-dwelling leukocytes involved both in normal immune responses and in those immunologic diseases marked by eosinophilia. Eosinophils have recognized roles in host defense against large non-phagocytosable parasites, in the generation of specific biologically active lipid mediators of inflammation, and, with excessive degranulation, in contributing to tissue dysfunction and damage. These roles reflect the capabilities of the eosinophil as an end-stage effector cell. The eosinophil, however, also has newly recognized additional capabilities and, in a fashion analogous to the macrophage, can function in collaborative interactions with lymphocytes and other cell types. Human eosinophils synthesize and express CD4 and specific cell adhesion proteins and can be induced to synthesize and express the class II MHC protein, HLA-DR. Eosinophils utilize CD4 to respond to CD4 binding ligands, including lymphocyte chemoattractant lymphokine (LCF), which is a potent eosinophil chemoattractant. Eosinophils utilize HLA-DR and can serve an antigen- presenting cells stimulating CD4+ lymphocytes. Eosinophils in tissues can elaborate cytokines, including transforming growth factor-alpha. These newly identified capabilities of eosinophils enable eosinophils to interact with and respond to lymphocytes, to be specifically recruited and mobilized into sites of inflammation, and to stimulate functions of lymphocytes and mesenchymal cells. Thus, in addition to functioning as an end-stage effector cell, the eosinophil can function in more dynamic, collaborative interactions with other cellular elements of the immune system. The proposed studies will investigate the various means by which eosinophils collaboratively interact with lymphocytes, monocytes and other cells in pulmonary immunologic diseases. Three aspects of the collaborative immunologic functions of human eosinophils will be studied. First, the functions of CD4 on eosinophils will be investigated to delineate both the mechanisms of LCF-induced, CD4-mediated intracellular signal transduction and the functional eosinophil responses elicited via CD4. Second, the expression and function of specific cell-surface proteins, including HLA-DR and cell adhesion molecules, that mediate interactions of eosinophils with lymphocytes, endothelial cells and other cells will be investigated. Third, the regulation and function of eosinophil cytokine elaboration will be evaluated. These investigations, which will study eosinophils from blood, bronchoalveolar lavage fluids and tissues, aim to define mechanisms that govern the collaborative immunologic roles of eosinophils as cellular participants interactive with other immunologic and tissue cells in pulmonary immunologic diseases.
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