We are studying the secretory and endocytic activities of mononuclear phagocytes (MP's) which are involved in all inflammatory disease states and are key elements for host defense against infectious agents and tumors a well as effector cells for tissue damage. This is a multidisciplinary proposal combining our knowledge of the Cell Biology, Biochemistry, Immunology and Pathology of the MP's. Both the secretion of inflammatory mediators and the recognition of foreignness are accomplished via receptor-ligand interactions. Focussing on the Fc and C3 receptors we wish to understand the ligand dependent signals, their transmembrane passage and the cytoplasmic events leading to the production of arachidonate metabolites and the internalization of plasma membrane. Membrane-membrane and membrane-protein interactions associated with phagosome-lysosome fusion and cell mediated cytotoxicity are being approached by ultrastructural, biophysical and immunological techniques. The nature of resident and emigratory macrophages of liver and spleen are studied after enzymatic dissociation of the organ and subsequent phenotypic and biochemical analysis in vitro. Appropriate infections and tumor models will allow us to quantitate the interactions between T cell subsets and MP's in granulomata of the liver and establish the mechanisms controlling their emigration, persistence and turnover. This will be facilitated by the ease of dissociating the liver into single cell suspensions and separating MP's and T cells. Kuppfer cells fail to secrete toxic oxygen intermediates and are permissive hosts for intracellular parasites. We wish to understand this selective inability to express the activated state and will examine underlying biochemical mechanisms and therapeutic delivery systems to reverse this defect. Murine models are being developed to study the bidirectional dialogue between MP's and classes of lipids and lipoproteins.
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