A comparative study into the mechanisms of action of anti-tumor necrosis factor alpha, anti-CD4, and combined anti-tumor necrosis factor alpha/anti-CD4 treatment in early collagen-induced arthritis

Objective. Anti-tumor necrosis factor alpha (anti-TNF alpha) therapy is ver y effective in rheumatoid arthritis (RA), whereas depleting anti-CD4 therap y 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 a nti-CD4 monoclonal antibodies (mAb), anti-TNF alpha mAb, or phosphate buffe red saline. Another group was given a combination of anti-TNF alpha plus an ti-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-TNF alpha significantly reduced the numbers of cells expressi ng TNF alpha, interleukin-1 alpha (IL-1 beta), 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 re duction in the expression of TNF alpha, IL-1 beta, VLA-4, and VCAM-1, but t his did not reach statistical significance. Depleting anti-CD4 was also sur prisingly ineffective in eliminating CD4+ T cells from the joint. Anti-TNF alpha therapy was also more effective than anti-CD4 in reducing Th1 activit y, as assessed by the production of interferon-gamma in lymph node cell cul tures. There was a synergistic relationship between anti-TNF alpha and anti -CD4 in the reduction of histologic score and inhibition of TNF alpha/Il-1 beta 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 activit y, This kind of analysis may prove useful in the testing of novel therapies for RA.