A drug commonly used to treat rheumatoid arthritis (RA), adalimumab (also known as Humira), has long been thought to exert its anti-inflammatory effects through specific binding to Tumor Necrosis Factor-α (TNF α), preventing it from interacting with TNF receptors. Patients with RA have elevated levels of TNF in their synovial fluid, which greatly contribute to inflammation and joint destruction, 2 hallmarks of RA.
Declines in levels of serum Interleukin-6 (Il-6), and acute phase reactants of inflammation are observed in RA patients treated with Humira, compared to untreated patients1.
A study published June 6, 2016 in the Journal of Experimental Medicine and conducted by Dao Xuan Nguyen, PhD and Michael Ehrenstein, PhD from University College London, shows evidence for a previously unknown mechanism whereby adalimumab exerts its anti-inflammatory effects2.
A subset of T helper cells, Th17, produces the highly inflammatory cytokine, Il-17 which has been implicated in the pathophysiology of RA and other auto-immune disorders. RA patients have elevated peripheral Th17 cells, which contribute to joint destruction. Il-17 can be produced by regulatory T cells (Treg cells) and displays resistance to Treg cell-mediated suppression of inflammation. During inflammation, Treg cells may become unstable and secrete enhanced levels of Il-17, rendering Il-17 a potential pharmacologic target for inflammatory diseases.
A previous study from the Ehrenstein laboratory showed that RA patients treated with adalimumab had higher Treg cell count than untreated patients, allowing for inhibition of Il-17 3. The authors hypothesized that in the absence of adalimumab, TNF could block Treg development. However, etanercept, a soluble TNF receptor as effective as adalimumab in treating RA, 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 adalimumab2.
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.
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.
2.Nguyen DX, Ehrenstein M Anti-TNF drives regulatory T cell expansion by paradoxically promoting membrane TNF–TNF-RII binding in rheumatoid arthritis. doi: 10.1084/jem.20151255
3.Mcgovern JL, Nguyen DX, Notley CA, Mauri C, Isenberg DA, Ehrenstein MR. Th17 cells are restrained by Treg cells via the inhibition of interleukin-6 in patients with rheumatoid arthritis responding to anti-tumor necrosis factor antibody therapy. Arthritis Rheum. 2012;64(10):3129-38.