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Rheumatology 2002; 41: 329-337
© 2002 British Society for Rheumatology
Original Papers |
The role of TNF-
in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera
Department of Orthopedic Surgery, Toyama Medical and Pharmaceutical University, Toyama,
1 Department of Pathology, Iwate Medical University, Iwate,
2 Department of Internal Medicine, Osaka University, Osaka, Japan and
3 Department of Rheumatology, King's College London, UK
Objective. In order to elucidate which cytokine preferentially stimulates the synovium in patients with rheumatoid arthritis (RA), we investigated the roles of tumour necrosis factor 
(TNF-) and interleukin 6 (IL-6) using SCID mice engrafted with human RA tissue (SCID-HuRAg).
Methods. The SCID-HuRAg mice were prepared according to our previously described method. First, SCID-HuRAg mice were treated with chimeric anti-TNF- monoclonal antibody (mAb, 100 µg/mouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 µg of recombinant TNF- or IL-6 (0.6 µg/h) was administered daily to mice using an osmium pump. The histological changes and serum cytokine levels were examined 4 weeks after the initial administration. Human immunoglobulin G (IgG) was administered to mice as a control.
Results. Synovial inflammatory cells were significantly decreased after the anti-TNF- mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF- administration. The levels of both IL-6 and TNF- in sera were significantly increased by recombinant TNF- administration, while TNF- levels were unchanged by IL-6 administration. This suggests that TNF- controls IL-6 production. Despite the profound changes in inflammation, we found no effects on bone and no articular cartilage damage was produced by TNF-.
Conclusion. This study provides strong evidence that TNF- is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF- regulates IL-6 production. However, other inflammatory pathways independent of TNF- may contribute to the bone and cartilage damage seen in RA.
KEY WORDS: Rheumatoid arthritis, SCID mouse, Tumour necrosis factor, Interleukin-6, Pathology.
Correspondence to: H. Matsuno, 2630 Sugitani, Toyama, Japan 930-0194.
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