Abstract
Results Ex vivo analysis of patients with RA on TNFi therapy revealed an enrichment of Th17 cells in peripheral blood compared to those on disease-modifying anti-rheumatic drugs or healthy controls. However, we also found an increase in IL-10-producing CD4+ T-cells. The enrichment in IL-17+ and IL-10+ CD4+ T-cells, including IL17+IL-10+ co-expressing CD4+ T-cells, was recapitulated in vitro by the addition of TNFi drugs (adalimumab, infliximab, etanercept, and certolizumab) to human monocyte/CD4+ T-cell co-cultures. IL-10 induction was independent of FcgR binding, IL-10 and CD4+CD25+ Tregs. TNFi-induced Th17 cells were functionally distinct as shown by an ability to modulate CD14+ monocytes in an IL-10-dependent manner. We report the identification of a transcription factor that is strongly associated with IL-10 expression in TNFi-induced IL-17+ CD4+ T-cells, and show that overexpression of this transcription factor drives IL-10 expression in primary CD4+ T-cells.
Highlights
TNF-a inhibitor (TNFi) therapy has revolutionized the treatment of immune-mediated inflammatory diseases, including rheumatoid arthritis (RA)
Ex vivo analysis of patients with RA on TNFi therapy revealed an enrichment of Th17 cells in peripheral blood compared to those on disease-modifying anti-rheumatic drugs or healthy controls
TNFi-induced Th17 cells were functionally distinct as shown by an ability to modulate CD14+ monocytes in an IL-10-dependent manner
Summary
TNF-inhibitor drugs regulate human pathogenic Th17 cells through induction of IL-10. Hayley G Evans1*, Nicola J Gullick, Gina J Walter, Urmas Roostalu, Klaus S Frederiksen, Jens G Gerwien, Andrew P Cope, Frederic Geissmann, Bruce W Kirkham, Leonie S Taams. From 7th European Workshop on Immune-Mediated Inflammatory Diseases Noordwijk aan Zee, the Netherlands. From 7th European Workshop on Immune-Mediated Inflammatory Diseases Noordwijk aan Zee, the Netherlands. 28-30 November 2012
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