THERAPEUTIC ACTIONS OF CYCLOSPORINE AND ANTITUMOR NECROSIS FACTOR-ALPHA IN COLLAGEN-INDUCED ARTHRITIS AND THE EFFECT OF COMBINATION THERAPY

Objective. To define the mechanisms of action of 2 novel drugs, cyclos porine and anti-tumor necrosis factor alpha (TNF alpha), in collagen-i nduced arthritis and to determine the effect of combination therapy. M ethods. Type II collagen-immunized DBA/1 mice with established arthrit is,were treated with cyclosporine alone, anti-TNF alpha alone, cyclosp orine plus anti-TNF alpha, or saline. Results. Cyclosporine was found to ameliorate arthritis, suppress interferon-gamma (IFN gamma) product ion by CD4+ T cells, and reduce TNF alpha expression in arthritic join ts. However, cyclosporine did not directly inhibit TNF alpha productio n by macrophages, indicating that the decrease in TNF alpha expression observed in vivo was probably an indirect consequence of the reductio n in type 1 T helper cell activity. Anti-TNF alpha also reduced IFN ga mma production by T cells, indicating that TNF alpha is involved in th e cellular immune response to collagen. Combined treatment with cyclos porine plus anti-TNF alpha! had an additive therapeutic effect. Conclu sion. Although cyclosporine and anti-TNF alpha target different points in the inflammatory pathway, there is an overlap in the consequences of their actions in vivo.