Antibodies against intercellular adhesion molecule-1 and lymphocyte function-associated antigen-1 prevent glomerular...

The involvement of adhesion molecules in the glomerular accumulation of inflammatory cells and subsequent glomerular injury was examined in WKY rats with nephrotoxic serum nephritis. This model is characterized by early infiltration of CD8-positive NK cells, followed by influx of monocytes/macrophages into the glomeruli. At day 1 and later, up-regulated expression of intercellular adhesion molecule-1 (ICAM-1) was observed exclusively in the glomerular endothelial cells in association with the influx of CD8-positive cells and monocytes/macrophages. These cells expressed lymphocyte function-associated Ag-1 (LFA-1). Repeated injection of mAb against rat ICAM-1 or alpha-subunit of LFA-1 (LFA-1 alpha) dose dependently prevented the development of proteinuria, the influx of these cells, and subsequent crescent formation in this nephrotoxic serum nephritis model. Furthermore, simultaneous administration of anti-ICAM-1 mAb and anti-LFA-1 alpha mAb exerted additive protective effects against urinary protein excretion and crescentic glomerulonephritis. Binding of anti-GBM antibody to the glomeruli and production of circulating anti-rabbit IgG antibody were unaffected by injection of these mAb. These results indicate that adhesion of CD8-positive cells and monocytes to glomerular endothelial cells through the LFA-1/ICAM-1 pathway is crucial for the initiation and subsequent progression of nephrotoxic serum nephritis in WKY rats.