Paradoxical Activation of TNF-Regulatory Functions by Adalimumab

Therapeutic anti-TNF antibodies, long thought to act primarily via blockade of proinflammatory soluble TNF, appear to also bind membrane-bound TNF supporting regulatory T-cell expansion suppressing further inflammation.

Adalimumab has long been thought to exert its anti-inflammatory effects primarily through specific binding to tumor necrosis factor-α (TNF-α), preventing it from interacting with TNF-receptors. Patients with rheumatoid arthritis (RA) have elevated levels of TNF in their synovial fluid, contributing to inflammation and joint destruction. Declines in levels of serum interleukin-6 (Il-6), and acute phase reactants of inflammation are observed in RA patients treated with adalimumab as compared to untreated patients.1

According to a new study published in the Journal of Experimental Medicine, conducted by Dao Xuan Nguyen, PhD and Michael Ehrenstein, PhD from University College London, supports a previously unknown mechanism whereby adalimumab also exerts its anti-inflammatory effects.2

A previous study by Dr Ehrenstein and colleagues showed that RA patients treated with adalimumab had higher Treg cell counts than untreated patients, allowing for inhibition of Il-17. 3 The authors hypothesized that in the absence of adalimumab, TNF could block Treg development. 

High Yield Data Summary

  • Adalimumab not only blocks soluble TNF, but also appears to enhance the immunosuppressive properties of membrane-bound TNF

However, etanercept, a soluble TNF receptor, did not have the same effect on Treg cell count. This observation prompted researchers to further investigate mechanisms of suppression of Th17 cells by Treg cells in response to adalimumab.2

Results from this study indicated that adalimumab, unlike etanercept, enhances TNF’s ability to induce anti-inflammatory T cell formation, by enhancing surface TNF expression on monocytes, and promoting their binding to Treg cells, thus conferring anti-inflammatory properties to T cells.

“The data presented here implicate an alternative interpretation, specifically that therapeutic anti-TNF antibodies paradoxically promote T reg cell TNF-RII signaling to drive their expansion,” the authors stated.

Summary and Clinical Applicability

Therapeutic anti-TNF antibodies, long thought to act primarily via blockade of proinflammatory soluble TNF, appear to also affect membrane-bound TNF, supporting Treg expansion suppressing further inflammation.


1. Kobayashi T, Yokoyama T, Ito S, et al. Periodontal and serum protein profiles in patients with rheumatoid arthritis treated with tumor necrosis factor inhibitor adalimumab. J Periodontol. 2014;85(11):1480-8.

This article originally appeared on Clinical Pain Advisor