Antibody blockade of TNF-α reduces inflammation and scarring in experimental crescentic glomerulonephritis

Antibody blockade of TNF-α reduces inflammation and scarring in experimental crescentic glomerulonephritis.BackgroundTumor necrosis factor-α (TNF-α) is a proinflammatory cytokine produced by macrophages, and by renal mesangial and tubular epithelial cells. It stimulates the release of interleukin (IL)-1β, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-β (TGF-β). Blockade of TNF-α is currently used clinically in several autoimmune inflammatory diseases. We hypothesised that blocking TNF-α with a monoclonal antibody would prevent inflammation and renal fibrosis in crescentic glomerulonephritis.MethodsNephrotoxic nephritis was induced in Wistar Kyoto (WKY) rats by intravenous injection of rabbit antirat glomerular basement membrane (GBM) nephrotoxic serum (NTS). Anti-TNF-α monoclonal antibody or saline was given intraperitoneally three times per week in four protocols: experiment 1, days 0 to 7; experiment 2, days 0 to 14 and days 4 to 14; experiment 3, days 4 to 28; and experiment 4, days 14 to 28.ResultsIn experiment 1, rats treated from disease induction had less glomerular fibrinoid necrosis and fewer glomerular macrophages at day 7. In experiment 2, rats treated from day 0 or day 4 showed improved renal function, as judged by serum creatinine, with a significant reduction in crescents. In experiment 3, anti-TNF-α treatment significantly reduced urine protein to creatinine ratio and urinary MCP-1 levels. Serum creatinine was preserved at both day 14 and day 28. Tubulointerstitial inflammation, glomerular and tubulointerstitial scarring, and markers of fibrosis [α-smooth muscle actin (α-SMA) and type IV collagen] were significantly less in treated rats at day 28. In experiment 4, serum creatinine was higher and tubulointerstitial scarring was less in delayed-treated animals.ConclusionNeutralization of endogenous TNF-α reduces glomerular inflammation, crescent formation, and tubulointerstitial scarring, with preservation of renal function, in experimental crescentic glomerulonephritis. TNF-α blockade is effective even when introduced at the time of maximum glomerular inflammation.