TNFalpha blockade in human diseases: mechanisms and future directions

Abstract

Tumor necrosis factor-alpha (TNFalpha) antagonists have shown remarkable efficacy in a variety of immune-mediated inflammatory diseases (IMIDs). Therapeutic scope and limitations of these agents are reviewed in a recently published article in the Journal. In spite of their therapeutic popularity, little is known about their modes of action in vivo and factors that limit their scope of therapeutic use. Intriguingly, while all TNFalpha antagonists including blocking antibodies and soluble receptors are effective in certain IMIDs, only anti-TNFalpha antibodies are effective in other IMIDs. Early efforts at understanding how TNFalpha antagonists act in IMIDs centered on their ability to neutralize soluble TNFalpha or to block TNF receptors from binding to their ligands. Subsequent studies suggested a role of complement-mediated lysis or antibody-dependent cell cytotoxicity in their therapeutic effects. More recent models postulate that TNFalpha blockers may act by affecting intracellular signaling, with the end result being a hastened cell cycle arrest, apoptosis, suppression of cytokine production, or improved Treg cell function. TNFalpha antagonists can also modulate the functions of myofibroblasts and osteoclasts, which might explain how TNFalpha antagonists reduce tissue damage in chronic IMIDs. Focusing on the human therapeutic experience, this analytical review will review the biology of mechanisms of action, the limiting factors contributing to disease restriction in therapeutic efficacy, and the mechanism and frequency of treatment-limiting adverse responses of TNFalpha antagonists. It is hoped that the overview will address the needs of clinicians to decide on optimal use, spur clinical innovation, and incite translational researchers to set priorities for in vivo human investigations.

Figure 1

Extracellular molecular targets of TNF antagonists in human diseases. Potential common targets in various diseases are shown on the left. Targets that have been specifically reported in rheumatoid arthritis (RA) and Crohn's disease (CD) are highlighted in the boxes on the right. Pathways in which TNF-antagonists block are shown by red symbol [2,23,113].

Figure 2

Reverse intracellular signaling cascade induced by the binding of anti-TNFAbs to trans-membrane TNF (tmTNF). This is one potential mechanism accounting for the in vitro effect of anti-TNF agents as distilled from several sources. See text for further details. Red=induced by anti-TNF binding to tmTNF.