Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
TNF-alpha Antagonist Therapy Leads to an Expansion of IL-17 Expressing CD4 T Cells Both In Vitro and In Vivo.
Evans2, Hayley G., Gullick3, Nicola J., Kirkham1, Bruce W., Taams3, Leonie S.
TNF-alpha is a highly pro-inflammatory cytokine, which contributes to inflammation and joint damage progression in patients with Rheumatoid Arthritis (RA). Use of TNF-alpha antagonists has had considerable success in the clinic, by reducing disease activity and inhibiting joint damage progression. We have previously demonstrated that TNF-alpha can induce IL-17 expression and secretion from CD4+ T cells when produced in combination with IL-1-beta by in vitro activated monocytes. IL-17 has also been shown to induce tissue inflammation and bone destruction in RA. In the present study we investigated how the presence of IL-17-producing CD4+ T cells is affected by TNF-alpha antagonist therapy.
PBMC and CD4+ T cells from healthy controls (n=13) or patients with RA (n=34) were stimulated ex vivo with PMA/ionomycin and analysed via intracellular flow cytometry and ELISA for their production of IL-17 and IFN-gamma. PBMC (0.5×106 in a 48 well plate) and CD4+ T cell/monocyte (0.5×106:0.5×106, in a 24 well plate) co-cultures were also cultured in the absence or presence of Infliximab, Etanercept or Adalimumab followed by stimulation and analysis via flow cytometry and ELISA.
The percentage of IL-17+ CD4+ T cells is significantly enriched in the blood of RA patients when compared to healthy controls (0.6±0.6% vs. 1.4±1.2%, p=0.003. When separated by treatment regimes, we observed a further enrichment of IL-17+ CD4+ T cells in patients treated with TNF-alpha antagonists compared to those on DMARD therapy (1.1±0.8% vs. 2.3±1.7%, p=0.02). This enrichment could not be explained by the method of stimulation, naïve/memory cell ratio, the age, sex, and disease duration or disease activity of the patients. Instead this may be a direct drug effect since in vitro experiments demonstrated that the presence of TNF-alpha antagonists can stimulate the expression of IL-17 by CD4+ T cells (63±41%, n=6). Finally, preliminary data indicate a rise in the percentage CD4+IL-17+ expressing T cells in the blood when measured ex vivo pre and post anti-TNF-alpha therapy.
Treatment of RA patients with TNF-alpha antagonists leads to an increase of Th17 cells in the peripheral blood. In vitro experiments suggest this may not simply be the result of re-distribution of joint Th17 cells. We propose that the presence of this primed pool of pro-inflammatory T cells may contribute to relapse of disease when anti-TNF-alpha therapy is ceased.
The authors acknowledge financial support from the Department of Health via the NIHR comprehensive Biomedical Research Centre at GSTT NHS Foundation Trust and King's College London.
To cite this abstract, please use the following information:
Evans, Hayley G., Gullick, Nicola J., Kirkham, Bruce W., Taams, Leonie S.; TNF-alpha Antagonist Therapy Leads to an Expansion of IL-17 Expressing CD4 T Cells Both In Vitro and In Vivo. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1838