Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis

J Clin Invest. 2001 Dec;108(12):1825-32. doi: 10.1172/JCI12097.


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-alpha, IL-6, and IFN-gamma 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.

MeSH terms

  • Animals
  • Arthritis / blood
  • Arthritis / therapy*
  • Collagen / immunology*
  • Glycoproteins / therapeutic use*
  • Immunoglobulin G / therapeutic use*
  • Intercellular Signaling Peptides and Proteins
  • Interferon-gamma / biosynthesis
  • Interleukin-18 / antagonists & inhibitors
  • Interleukin-18 / blood
  • Interleukin-18 / physiology*
  • Interleukin-6 / biosynthesis
  • Interleukin-6 / blood
  • Male
  • Mice
  • Mice, Inbred DBA
  • Recombinant Proteins / therapeutic use
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Glycoproteins
  • Immunoglobulin G
  • Intercellular Signaling Peptides and Proteins
  • Interleukin-18
  • Interleukin-6
  • Recombinant Proteins
  • Tumor Necrosis Factor-alpha
  • interleukin-18 binding protein
  • Interferon-gamma
  • Collagen