jci.org
J Clin Invest, December 2001, Volume 108, Number 12, 1825-1832
Copyright ©2001 by the American Society for Clinical Investigation
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Article
Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis
Christine Plater-Zyberk1, Leo A.B. Joosten2, Monique M.A. Helsen2, Pascale Sattonnet-Roche1, Christiane Siegfried1, Sami Alouani1, Fons A.J. van de Loo2, Pierre Graber1, Shuki Aloni3, Rocco Cirillo4, Erik Lubberts2, Charles A. Dinarello5, Wim B. van den Berg2 and Yolande Chvatchko1
1 Serono Pharmaceutical Research Institute, Geneva, Switzerland 2 Rheumatology Research Laboratory, University Medical Center Nijmegen, Nijmegen, The Netherlands 3 InterPharma Laboratories, Nes Ziona, Israel 4 Istituto Di Ricerche Biomedche Antoine Marxer, Collereto Giacosa, Italy 5 Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA
Address correspondence to: Yolande Chvatchko, Serono Pharmaceutical Research Institute 14, Chemin des Aulx CH-1228 Plan-les-Ouates, Geneva, Switzerland. Phone: 41-22-706-9792; Fax: 41-22-794-6965; E-mail: yolande.chvatchko@serono.com.
Received for publication January 3, 2001, and accepted in revised form October 22, 2001.
Two distinct IL-18 neutralizing strategies, i.e. a rabbit polyclonal anti-mouse IL-18 IgG and a recombinant human IL-18 binding protein (rhIL-18BP), were used to treat collagen-induced–arthritic DBA/1 mice after clinical onset of disease. The therapeutic efficacy of neutralizing endogenous IL-18 was assessed using different pathological parameters of disease progression. The clinical severity in mice undergoing collagen-induced arthritis was significantly reduced after treatment with both IL-18 neutralizing agents compared to placebo treated mice. Attenuation of the disease was associated with reduced cartilage erosion evident on histology. The decreased cartilage degradation was further documented by a significant reduction in the levels of circulating cartilage oligomeric matrix protein (an indicator of cartilage turnover). Both strategies efficiently slowed disease progression, but only anti–IL-18 IgG treatment significantly decreased an established synovitis. Serum levels of IL-6 were significantly reduced with both neutralizing strategies. In vitro, neutralizing IL-18 resulted in a significant inhibition of TNF-, IL-6, and IFN- secretion by macrophages. These results demonstrate that neutralizing endogenous IL-18 is therapeutically efficacious in the murine model of collagen-induced arthritis. IL-18 neutralizing antibody or rhIL-18BP could therefore represent new disease-modifying anti-rheumatic drugs that warrant testing in clinical trials in patients with rheumatoid arthritis. |
