Intervention of crescentic glomerulonephritis by antibodies to monocyte chemotactic and activating factor (MCAF/MCP‐1)

Abstract

We investigated the pathophysiological role of a potent macrophage (M(phi)) chemotactic cytokine (chemokine), monocyte chemotactic and activating factor/monocyte chemoattractant protein-1 (MCAF/MCP-1), in an animal model of crescentic glomerulonephritis. Administration of a small dose of nephrotoxic sera induced severe proliferative and necrotizing glomerulonephritis, with crescentic formation in the early phase and glomerulosclerosis in the later phase, in Wistar-Kyoto rats. MCAF/MCP-1 protein was detected immunohistochemically in glomeruli, vascular endothelial cells, and tubular epithelial cells in the early phase of injured kidney tissues but not in normal ones. Anti-MCAF/MCP-1 antibodies decreased the number of M(phi) in glomeruli, and prevented crescentic formation and the fusion of epithelial cell foot process in nephritic rats, thereby decreasing the excreted amounts of protein to normal levels on days 3 and 6. Furthermore, anti-MCAF/MCP-1 antibodies remarkably reduced glomerulosclerosis and improved renal dysfunction as well as proteinuria in the later phase (56 days). These results indicate that MCAF/MCP-1 essentially participates in the impairment of renal functions associated with crescentic glomerulonephritis by recruiting and activating M(phi).

Mononuclear Cell-Infiltrate Inhibition by Blocking Macrophage-Derived Chemokine Results in Attenuation of Developing Crescentic Glomerulonephritis

“…Accordingly, in anti-GBM GN in WKY rats, neutralization of MCP-1 reduced glomerulosclerosis and improved renal function in the later phase of the disease. 37 In a similar model of GN in mice, neutralization of antibodies to MCP-1 resulted in a decrease in the deposition of collagen. 12 Nonetheless, Fujinaka et al 13 found a significant suppression of glomerular infiltration and proteinuria by blocking MCP-1 at the early phase of the disease but not at day 8.…”

“…35,36 In this model of GN, enhanced gene expression of chemokines has been demonstrated; however, most of the studies have focused on the acute phase of the disease. 13,37 Furthermore, studies with neutralizing antibodies and blocking reagents targeted acute glomerular injury and were used at day l, or at the same time as anti-GBM Ab administration, before the development of the disease.…”

CC Chemokine Ligand 5/RANTES Chemokine Antagonists Aggravate Glomerulonephritis Despite Reduction of Glomerular Leukocyte Infiltration

“…Chemokine blockade with specific Abs or chemokine antagonists has been shown to reduce monocyte influx and proteinuria in some of these models (7,10,11). Therefore, chemokine antagonism is thought to be a promising therapeutic approach for proliferative GN as well as for many other inflammatory diseases (12)(13)(14)(15)(16).…”

Small molecule inhibitor of HIV-1 cell fusion blocks chemokine receptor-mediated function

“…Antibody neutralization of MCP-1 has been shown to improve glomerulonephritis in nephritic rats [10]. Chemokines modified to behave as antagonists have been shown to be effective against arthritis in a murine model and asthma in a guinea pig model [11,12].…”