TNF and TNF receptors as therapeutic targets for rheumatic diseases and beyond

The TNF-TNF receptor signalling network has pleiotropic effects that can both promote and protect against immune-mediated diseases. Modulation of this network through the use of TNF receptor-targeting biologic drugs holds promise for treating various diseases, including TNF inhibitor-refractory diseases. The cytokine TNF signals via two distinct receptors, TNF receptor 1 (TNFR1) and TNFR2, and is a central mediator of various immune-mediated diseases. Indeed, TNF-neutralizing biologic drugs have been in clinical use for the treatment of many inflammatory pathological conditions, including various rheumatic diseases, for decades. TNF has pleiotropic effects and can both promote and inhibit pro-inflammatory processes. The integrated net effect of TNF in vivo is a result of cytotoxic TNFR1 signalling and the stimulation of pro-inflammatory processes mediated by TNFR1 and TNFR2 and also TNFR2-mediated anti-inflammatory and tissue-protective activities. Inhibition of the beneficial activities of TNFR2 might explain why TNF-neutralizing drugs, although highly effective in some diseases, have limited benefit in the treatment of other TNF-associated pathological conditions (such as graft-versus-host disease) or even worsen the pathological condition (such as multiple sclerosis). Receptor-specific biologic drugs have the potential to tip the balance from TNFR1-mediated activities to TNFR2-mediated activities and enable the treatment of diseases that do not respond to current TNF inhibitors. Accordingly, a variety of reagents have been developed that either selectively inhibit TNFR1 or selectively activate TNFR2. Several of these reagents have shown promise in preclinical studies and are now in, or approaching, clinical trials.