In vivo neutralization of TNF-alpha promotes humoral autoimmunity by preventing the induction of CTL

Neutralization of TNF-alpha in humans with rheumatoid arthritis or Crohn's disease has been associated with the development of humoral autoimmunity. T o determine the effect of TNF-alpha neutralization on cell-mediated and hum oral-mediated responses, we administered anti-TNF-alpha mAb to mice undergo ing acute graft-vs-host disease (GVHD) using the parent-into-F-1 model. In vivo neutralization of TNF-alpha blocked the lymphocytopenic features chara cteristic of acute GVHD and induced a lupus-like chronic GVHD phenotype (ly mphoproliferation and autoantibody production). These effects resulted from complete inhibition of detectable antihost CTL activity and required the p resence of anti-TNF-alpha mAb for the first 4 days after parental cell tran sfer, indicating that TNF-alpha plays a critical role in the induction of C TL. Moreover, an in vivo blockade of TNF-alpha preferentially inhibited the production of IFN-gamma and blocked IFN-gamma -dependent up-regulation of Fas; however, cytokines such as IL-10, M-6, or IL-4 were not inhibited. The se results suggest that a therapeutic TNF-alpha blockade may promote humora l autoimmunity by selectively inhibiting the induction of a CTL response th at would normally suppress autoreactive B cells.