The role of TNF‐α in the pathogenesis of inflammation and joint destruction in rheumatoid arthritis (RA): a study using a human RA/SCID mouse chimera

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 a (TNF-a) 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-a monoclonal antibody (mAb, 100 mgumouse) and histological changes were examined 4 weeks after the initial treatment. Secondly, a total of 100 mg of recombinant TNF-a or IL-6 (0.6 mguh) 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-a mAb treatment; conversely, the degree of synovial inflammation was significantly exacerbated by TNF-a administration. The levels of both IL-6 and TNF-a in sera were significantly increased by recombinant TNF-a administration, while TNF-a levels were unchanged by IL-6 administration. This suggests that TNF-a 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-a. Conclusion. This study provides strong evidence that TNF-a is a key molecule in the control of the inflammatory changes that occur in the RA synovium. In addition, TNF-a regulates IL-6 production. However, other inflammatory pathways independent of TNF-a may contribute to the bone and cartilage damage seen in RA. Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by hyperplasia of the synovium and an excess of inflammatory cells, leading to progressive destruction of the joints. In RA, several cytokines, e.g. interleukin (IL)-1, IL-6, IL-8, IL-12, IL-17, tumour necrosis factor-a (TNF-a), interferon-c (IFN-c) and granulocyte‐macrophage colony-stimulating factor (GM-CSF), are involved in almost all aspects of articular inflammation and destruction w1x. TNF-a has been considered a pivotal cytokine in the pathogenesis of RA, as significant clinical and laboratory evidence has been obtained by TNF-a blockade w1‐3x. Moreover, it has been verified that neutralized monoclonal antibodies (mAb) against TNF-a can reduce the production of other proinflammatory cytokines, such as IL-1 and GM-CSF, in cultured RA synovia w4x .I n the clinical trials performed to date, anti-TNF-a mAb has been effective in the majority of treated RA patients. Moreover, anti-TNF-a mAb may reduce tissue perfusion in the inflamed synovium, according to the results