Premium
Combined interleukin 1 and tumour necrosis factor α blockade in rat crescentic anti‐glomerular basement membrane glomerulonephritis
Author(s) -
Lan Hui Y,
Song Qing,
NikolicPaterson David J,
Tesch Greg H,
Mu Wei,
Atkins Robert C
Publication year - 2001
Publication title -
nephrology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.752
H-Index - 61
eISSN - 1440-1797
pISSN - 1320-5358
DOI - 10.1046/j.1440-1797.2001.00056.x
Subject(s) - medicine , glomerulonephritis , blockade , cytokine , proteinuria , glomerular basement membrane , tumor necrosis factor alpha , basement membrane , rapidly progressive glomerulonephritis , endocrinology , infiltration (hvac) , renal function , saline , receptor antagonist , antagonist , receptor , pathology , kidney , physics , thermodynamics
SUMMARY: Studies in experimental models have established that blockade of either interleukin 1 (IL‐1) or tumour necrosis factor α (TNF‐α) is effective in suppressing crescentic glomerulonephritis. However, it is not known whether simultaneous blockade of both cytokines will provide additional disease suppression compared with that produced by single cytokine blockade. We have addressed this question in a study of accelerated crescentic anti‐glomerular basement membrane (GBM) glomerulonephritis in the rat. Groups of six animals were treated with an IL‐1 receptor antagonist (IL‐1ra), TNF‐α‐binding protein (TNFbp), IL‐1ra + TNFbp (combined) or saline (control) from the time of anti‐GBM serum injection until being killed, 10 days later. Saline‐treated animals developed crescentic glomerulonephritis with tubulointerstitial damage, heavy proteinuria and renal impairment. Compared with saline, treatment with either IL‐1ra or TNFbp alone resulted in significant suppression of crescent formation (3.0% and 3.3%, respectively, vs. 21.0%; both P < 0.001 vs. control), tubulointerstitial leucocytic infiltration (262 ± 31 and 282 ± 32 cells/mm 2 vs. 481 ± 71 cells/mm 2 ; both P < 0.001 vs. control) and proteinuria (167 ± 44 and 164 ± 23 mg/24 h vs. 279 ± 36 mg/24 h; both P < 0.001 vs. control) and prevented the loss of renal function. Combined IL‐1ra and TNFbp treatment resulted in a virtually identical degree of disease suppression as individual cytokine blockade in terms of crescent formation (2.7%), interstitial leucocytic infiltration (274 ± 45 cells/mm 2 ), proteinuria (190 ± 18 mg/24 h) and renal function preservation. In conclusion, this study has demonstrated that blockade of either IL‐1 or TNF‐α alone substantial suppresses experimental crescentic glomerulonephritis to a similar extent to that achieved by simultaneous blockade of both cytokines. These findings provide a rationale for the use of cytokine monotherapy, rather than multiple cytokine blockade, in the treatment of human crescentic glomerulonephritis.