NEW YORK (Reuters Health)—The anti-tumor necrosis factor (TNF) antibody adalimumab drives regulatory T cell (Treg) expansion in rheumatoid arthritis (RA) by binding to membrane TNF, researchers from the UK report.
“These results show that adalimumab enhances the anti-inflammatory actions of TNF to increase regulatory T cell activity,” Dr. Michael R. Ehrenstein from University College London, tells Reuters Health by email. “The data also supports the notion that membrane TNF stimulates the actions of regulatory T cells.”
Dr. Ehrenstein and Dr. Dao Xuan Nguyen showed previously that adalimumab, but not etanercept (a soluble TNF receptor), increased Treg cell numbers in patients with RA and that these Treg cells could suppress the highly inflammatory cytokine interleukin-17 (IL-17).
It was unclear, however, why etanercept, which was equally effective for treating RA, lacked Treg cell modulatory properties, so they undertook further studies.
After showing once again that adalimumab increased functionally suppressive Treg cells in rheumatoid arthritis patients, they demonstrated that adalimumab bound to membrane TNF expressed by rheumatoid arthritis monocytes and promoted binding between monocyte membrane TNF and TNF receptor II (TNF-RII) expressed by Treg cells.
This interaction triggered expansion of the Treg cell subset, according to the June 6 online report in the Journal of Experimental Medicine.
Adalimumab enhanced IL-2 production and increased STAT5 phosphorylation, which were required for adalimumab-driven Treg cell expansion.
These effects were not reproduced by exposure to etanercept.
“It would have been predicted that adalimumab inhibited the binding of its target,” Dr. Ehrenstein says. “In this way adalimumab blocks the inflammatory actions of soluble TNF but enhances the anti-inflammatory effects of membrane TNF at least with respect to the latter’s interaction with TNF receptor II expressed on regulatory T cells.”
“Also of relevance, adalimumab appeared to achieve this effect only in a narrow concentration range, which coincided with serum concentrations in patients responding to adalimumab,” he explains.
“Therefore, anti-TNF antibodies appear to be the first example of a therapeutic cytokine inhibitor that simultaneously boosts the pro-resolution forces driven by that pathway whilst still blocking the harmful actions of TNF, thereby highlighting a novel therapeutic paradigm,” Dr. Ehrenstein says. “This could have implications for other therapeutic antibodies used for a wide variety of indications.”
“Greater understanding of biologic therapies and their mechanisms of action could lead to the development of novel therapeutic approaches as well as defining biomarkers of disease response,” Dr. Ehrenstein says. “If regulatory T cells could be harnessed in such a way that disease does not return when therapy is stopped, this could lead to long-term disease remission.”