Deexyspergualin (DSP) is a potent immunosuppressive drug which Inhibits acute renal allograft rejection and the development of experimental anti-GBM glomerulonephritis (GN). To investigate the mechanism by which DSP suppresses renal macrophage accumulation, we examined the effect of DSP treatment on osteopontin (OPN) expression, a monocyte chemotactic and adhesion molecule. Passive accelerated anti-GBM GN was induced in rats by priming with rabbit IgG, followed 5 days later by injection of rabbit-anti-GBM serum (day 0). Groups of five rats were treated with DSP (5mg/kg i.p. daily) or saline (untreated) from day 0 until being killed on days 1, 7, 14 or 21. Saline treated animals developed severe proteinuria and a loss of GFR. Antibody staining showed a marked pregulation of renal OPN expression which was associated with focal macrophage accumulation and renal damage, such as crescent formation and tubular lesions. DSP treatment significantly inhibited glomerular and tubulointerstitial OPN expression 75-85%, p<0.001). This was associated with a marked reduction in glomerular and interstitial macrophage accumulation (50% and 80%, respectively, p<0.001) and suppression of renal damage, including crescent formation (90%↓) and tubular atrophy. Ih conclusion, this study has identified that suppression of OPN expression is an importantmechanism by which DSP inhibits macrophage-mediated renal injury in experimental crescentic GN.