Cellular and Molecular Life Sciences CMLS

, Volume 57, Issue 10, pp 1457–1470 | Cite as

Anti-interleukin-1 and anti-tumor necrosis factor-α synergistically inhibit adjuvant arthritis in Lewis rats

  • U. Feige*
  • Y.-L. Hu
  • J. Gasser
  • G. Campagnuolo
  • L. Munyakazi
  • B. Bolon

Abstract.

Interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α) play dominant roles in mediating the progression of many inflammatory joint diseases, including rheumatoid arthritis in humans, collagen-induced arthritis in mice and rats, and adjuvant arthritis in rats. Blockade of either cytokine partially controls these diseases. The present study investigated the value of combination anti-cytokine therapy in arthritis: the efficacy of IL-1 receptor antagonist (IL-1ra) and 30 kDa polyethylene glycol (PEG)-conjugated soluble TNF receptor type I (PEG sTNF-RI) given together was assessed in Lewis rats with adjuvant arthritis. Administration of either IL-1ra or PEG sTNF-RI partially alleviated joint inflammation, loss of bone mineral density, and loss of body weight. In contrast, combination of these anti-cytokine treatments exhibited a synergistic capacity to inhibit these changes, even when combining doses of IL-1ra and PEG sTNF-RI that did not affect lesion severity when used alone. Statistical analysis of these adjuvant arthritis data using the isobologram method proved that IL-1ra and PEG sTNF-RI were clearly synergistic in inhibiting inflammation, loss of bone mineral density, loss of body weight, and histopathologic parameters of inflammation and joint destruction. These results suggest that treating autoimmune arthritic diseases with combinations of anti-IL-1 and anti-TNF molecules will achieve superior efficacy compared to the use of a single class of anti-cytokine agent and may allow for dose reductions that could prove useful in minimizing potential side effects.

Key words. Rheumatoid arthritis; interleukin 1; tumor necrosis factor; cytokine; rat; adjuvant arthritis; IL-1ra; soluble receptor. 

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Copyright information

© Birkhäuser Verlag Basel, 2000

Authors and Affiliations

  • U. Feige*
    • 1
  • Y.-L. Hu
    • 1
  • J. Gasser
    • 1
  • G. Campagnuolo
    • 1
  • L. Munyakazi
    • 2
  • B. Bolon
    • 1
  1. 1.Department of Pharmacology/Pathology, Amgen, One Amgen Center Drive, M/S 15-2-A, Thousand Oaks (California 91320-1789, USA), Fax +1 805 499 75 06, e-mail: ufeige@amgen.com US
  2. 2.Department of Biostatistics, Amgen, Thousand Oaks (California 91320-1789, USA)US

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