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


CONCLUSIONS
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.
Khan
Sarah B
SB
Renal Section and Department of Histopathology, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, United Kingdom.
Cook
H Terence
HT
Bhangal
Gurjeet
G
Smith
Jennifer
J
Tam
Frederick W K
FW
Pusey
Charles D
CD
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001485:Basement Membrane / Q000276:immunology; D003404:Creatinine / Q000097:blood; D005921:Glomerulonephritis / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D007678:Kidney Glomerulus / Q000276:immunology; D008297:Male; D011817:Rabbits; D051381:Rats; D011921:Rats, Inbred WKY; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors*
D000911:Antibodies, Monoclonal; D014409:Tumor Necrosis Factor-alpha; D003404:Creatinine