Multiple Modes of Action of Anti-TNF-α Antibodies for Inflammatory Bowel Diseases Beyond TNF-α Neutralization.

Inflammatory bowel diseases (IBDs), chronic inflammatory disorders of the gastrointestinal tract, are classified into Crohn's disease (CD) and ulcerative colitis (UC). Despite differing clinical manifestations, both CD and UC share a common immunopathogenesis, involving excessive production of proinflammatory cytokines by macrophages and dendritic cells. Tumor necrosis factor-α (TNF-α), interleukin-12 (IL-12), and IL-23 are prototypical proinflammatory cytokines associated with CD and UC development, and biologics targeting these cytokines are widely used for treating patients with IBD. Antibodies (Abs) against IL-12 and IL-23 decrease intestinal inflammation by binding to the soluble forms of IL-12 and IL-23, respectively. Notably, anti-TNF-α Abs induce remission by neutralizing soluble TNF-α as well as membrane-bound TNF-α (mTNF-α). The binding of anti-TNF-α Abs to mTNF-α enables the diverse functions of IBD-specific TNF-α-inhibitors. Multiple modes of action of anti-TNF-α Abs for IBD include complement-dependent cytotoxicity, Ab-dependent cellular cytotoxicity, apoptosis of cells expressing mTNF-α, apoptosis of lamina propria T cells, and induction of regulatory T cells and macrophages. In this article, we introduce the diverse actions of anti-TNF-α Abs beyond TNF-α neutralization and discuss how these unique properties of anti-TNF-α Abs contribute to the efficient downregulation of IBD-associated inflammation.