HUMAN BLOOD MONOCYTE RECEPTOR EXPRESSION AND MODULATION

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Monocyte/macrophage Fc (IgG) and C3 receptors are important in host defense and in the pathophysiology of several hematologic diseases. Enhancement of their activity facilitates the ability of these cells to eliminate microorganisms. Inhibition of their activity improves the clinical status of patients with autoimmune hemolytic anemia and thrombocytopenia. Our goals in this research proposal are to delineate biochemical, immunologic and pharmacologic mechanisms which modulate the expression of these receptors. We will study Fc (IgG) and C3 receptor expression by analyzing the binding by monocytes/macrophages of 1) radiolabeled IgG and C3b monomer and oligomer and 2) erythrocytes coated with defined amounts of IgG, C3b and C3bi. We will determine the effect of C3b receptor perturbation on the number and affinity of monocyte/macrophage binding sites for monomeric and oligomeric IgG. We will also examine the effect of Fc (IgG) receptor perturbation on the number and affinity of monocyte/macrophage binding sites for C3b monomer and dimer. We will define the mechanisms by which a synthetic N-formyl oligopeptide, similar to that produced by bacteria, augments Fc (IgG) receptor activity and determine its effect on C3b receptor expression. We will also analyze the effect of an important endogenously derived mediator, histamine, on the expression of these surface receptors. Our preliminary data indicate that histamine does alter Fc (IgG) receptor expression. We will determine the mechanisms by which corticosteroids, commonly utilized pharmacologic agents in hematologic disease, modulate monocyte/macrophage Fc (IgG) and C3 receptor expression. We will examine the capacity of steroid analogues to enhance or inhibit the expression of these receptors. In these studies we will also use our in vivo animal model to examine modulation of macrophage Fc (IgG) and C3 receptor activity. Finally, we will examine the capacity of alterations in monocyte/macrophage membrane cholesterol/phospholipid to modulate Fe (IgG) and C3b receptor expression. These studies should be helpful in understanding the mechanisms by which monocyte and macrophage receptor expression is altered in human disease. Furthermore, they should be helpful in developing approaches to modulate such receptor expression in vitro and in vivo.