Most types of human as well as experimental glomerulonephritis are characterized by leukocyte (neutrophil. monocyte/macrophage) infiltration with the release of inflammatory mediators such as oxidants and proteases from these cells responsible for much of the glomerular injury. The mechanism by which these leukocytes are recruited from the circulation and localize in the glomeruli is unknown and is the focus of this research proposal. We hypothesize that leukocyte adhesion molecules (integrins) and their corresponding ligands expressed on resident glomerular cells (endothelial and mesangial) are necessary not only for leukocyte localization in the glomerulus but also for leukocyte mediated injury to the resident glomerular cells. The proposed studies to address this hypothesis will be two-fold in nature. We will use the classic model of anti-GBM nephritis in the rat to look at the role of adhesion molecules in vivo. This model is well characterized with a neutrophil dependent heterologous phase and a later macrophage dependent autologous phase. In both phases we will look for the upregulation of ELAM-1, VCAM-1, and ICAM-1 in the glomeruli and how this correlates with leukocyte infiltration. We will determine directly the importance of these adhesion molecules in this model by using specific monoclonal antibodies to ELAM-1, VCAM-1, and ICAM-1 as well as the leukocyte integrins CD18 and CD11b with our preliminary studies showing a protective effect. We will also explore the hypothesis that a primary biologic effect of cytokines such as TNFalpha and IL-1 is upregulation of these adhesion molecules. To address this we will determine if direct infusion of these cytokines induces upregulation of adhesion molecules in glomeruli and also conversely if specific antibodies to these cytokines inhibits the glomerular injury by preventing the upregulation of these molecules. In correlative in vitro studies we will determine if inflammatory mediators such as oxygen radicals and cytokines upregulate ELAM-1, VCAM-1, and ICAM-1 on mesangial and endothelial cells in culture. In addition, we will determine if oxidants upregulate integrin expression on neutrophils and monocytes and the effect of the leukocyte integrin antibodies; anti-CD18 and CD11b on leukocyte dependent killing of endothelial and mesangial cells. Our preliminary studies show that mesangial cells express adhesion molecules similar to the endothelial cells and that these adhesion molecules are important not only for adherence but also for leukocyte mediated cytotoxicity. The proposed studies as outlined above should provide new and useful information on the role of adhesion molecules in glomerulonephritis. If in fact adhesion molecules turn out to be as important in the pathogenesis of this disease as our preliminary studies suggest then specific """"""""anti-adhesion"""""""" therapy using monoclonal; antibodies could have a beneficial effect in the treatment of glomerulonephritis.
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