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

Abstract

BACKGROUND:

Tumor necrosis factor-alpha (TNF-alpha) is a proinflammatory cytokine produced by macrophages, and by renal mesangial and tubular epithelial cells. It stimulates the release of interleukin (IL)-1beta, monocyte chemoattractant protein-1 (MCP-1), and transforming growth factor-beta (TGF-beta). Blockade of TNF-alpha is currently used clinically in several autoimmune inflammatory diseases. We hypothesised that blocking TNF-alpha with a monoclonal antibody would prevent inflammation and renal fibrosis in crescentic glomerulonephritis.

METHODS:

Nephrotoxic nephritis was induced in Wistar Kyoto (WKY) rats by intravenous injection of rabbit antirat glomerular basement membrane (GBM) nephrotoxic serum (NTS). Anti-TNF-alpha 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.

RESULTS:

In 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-alpha 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 [alpha-smooth muscle actin (alpha-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.

CONCLUSION:

Neutralization of endogenous TNF-alpha reduces glomerular inflammation, crescent formation, and tubulointerstitial scarring, with preservation of renal function, in experimental crescentic glomerulonephritis. TNF-alpha blockade is effective even when introduced at the time of maximum glomerular inflammation.

• Authors: Sarah B Khan, H Terence Cook, Gurjeet Bhangal, Jennifer Smith, Frederick W K Tam, Charles D Pusey
• Journal: Kidney international (Kidney Int) Vol. 67 Issue 5 Pg. 1812-20 (May 2005) ISSN: 0085-2538 [Print] United States
• PMID: 15840028 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Tumor Necrosis Factor-alpha
• Creatinine

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Basement Membrane (immunology)
• Creatinine (blood)
• Glomerulonephritis (etiology, immunology, pathology, therapy)
• Kidney Glomerulus (immunology)
• Male
• Rabbits
• Rats
• Rats, Inbred WKY
• Time Factors
• Tumor Necrosis Factor-alpha (antagonists & inhibitors)