A comparative study into the mechanisms of action of anti–tumor necrosis factor α, anti-CD4, and combined anti–tumor necrosis factor α/anti-CD4 treatment in early collagen-induced arthritis
Abstract
Objective
Anti–tumor necrosis factor α (anti-TNFα) therapy is very effective in rheumatoid arthritis (RA), whereas depleting anti-CD4 therapy is relatively ineffective. To explain the differences in efficacy between these 2 therapies, we used an animal model of RA to compare their effects on different aspects of the disease process.
Methods
Mice with collagen-induced arthritis were treated with depleting anti-CD4 monoclonal antibodies (mAb), anti-TNFα mAb, or phosphate buffered saline. Another group was given a combination of anti-TNFα plus anti-CD4. The treatments were compared for their ability to down-regulate the expression of proinflammatory cytokines and adhesion molecules, reduce the cellularity of the joint, and inhibit Th1 activity.
Results
Anti-TNFα significantly reduced the numbers of cells expressing TNFα, interleukin-1β (IL-1β), very late activation antigen 4 (VLA-4), vascular cell adhesion molecule 1 (VCAM-1), and numbers of CD4+ T cells and macrophages in the joint. Anti-CD4 treatment led to a small reduction in the expression of TNFα, IL-1β, VLA-4, and VCAM-1, but this did not reach statistical significance. Depleting anti-CD4 was also surprisingly ineffective in eliminating CD4+ T cells from the joint. Anti-TNFα therapy was also more effective than anti-CD4 in reducing Th1 activity, as assessed by the production of interferon-γ in lymph node cell cultures. There was a synergistic relationship between anti-TNFα and anti-CD4 in the reduction of histologic score and inhibition of TNFα/IL-1β expression in the joints.
Conclusion
The efficacy of the 3 treatments correlated with their ability to modulate the expression of inflammatory cytokines and adhesion molecules in the joint, reduce the cellularity of the joint, and inhibit Th1 activity. This kind of analysis may prove useful in the testing of novel therapies for RA.
