Combined interleukin 1 and tumour necrosis factor alpha blockade in rat crescentic anti-glomerular basement membrane glomerulonephritis

Studies in experimental models have established that blockade of either int erleukin 1 (IL-1) or tumour necrosis factor alpha (TNF-alpha) is effective in suppressing crescentic glomerulonephritis. However, it is not known whet her simultaneous blockade of both cytokines will provide additional disease suppression compared with that produced by single cytokine blockade. We ha ve addressed this question in a study of accelerated crescentic anti-glomer ular basement membrane (GBM) glomerulonephritis in the rat. Groups of six a nimals were treated with an IL-1 receptor antagonist (IL-1ra), TNF-alpha -b inding protein (TNFbp), IL-1ra + TNFbp (combined) or saline (control) from the time of anti-GBM serum injection until being killed, 10 days later. Sal ine-treated animals developed crescentic glomerulonephritis with tubulointe rstitial damage, heavy proteinuria and renal impairment. Compared with sali ne, treatment with either IL-1ra or TNFbp alone resulted in significant sup pression of crescent formation (3.0% and 3.3%, respectively, vs. 21.0%; bot h 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 f unction. Combined IL-1ra and TNFbp treatment resulted in a virtually identi cal 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 prese rvation. In conclusion, this study has demonstrated that blockade of either IL-1 or TNF-alpha alone substantial suppresses experimental crescentic glo merulonephritis to a similar extent to that achieved by simultaneous blocka de of both cytokines. These findings provide a rationale for the use of cyt okine monotherapy, rather than multiple cytokine blockade, in the treatment of human crescentic glomerulonephritis.