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, 171 (3), 237-42

Effect of interleukin-6 Receptor Blockade on the Balance Between Regulatory T Cells and T Helper Type 17 Cells in Rheumatoid Arthritis Patients

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Effect of interleukin-6 Receptor Blockade on the Balance Between Regulatory T Cells and T Helper Type 17 Cells in Rheumatoid Arthritis Patients

B Pesce et al. Clin Exp Immunol.

Abstract

A new paradigm has emerged relating the pathogenesis of rheumatoid arthritis (RA), focused on the balance between T helper type 17 cells and regulatory T cells (T(regs) ). In humans, both subpopulations depend on transforming growth factor (TGF)-β for their induction, but in the presence of inflammatory cytokines, such as interleukin (IL)-6, the generation of Th17 is favoured. Tocilizumab is a therapeutic antibody targeting the IL-6 receptor (IL-6R), which has demonstrated encouraging results in RA. The aim of this study was to evaluate the effect of tocilizumab on Th1 cells, Th17 cells, IL-17 and interferon (IFN)-γ double secretors Th17/Th1 cells, and T(regs) in RA patients. Eight RA patients received tocilizumab monthly for 24 weeks and blood samples were obtained every 8 weeks to study T cell populations by flow cytometry. The frequency of Th17 cells, Th1 cells and Th17/Th1 cells was evaluated in peripheral blood mononuclear cells (PBMCs) activated in vitro with a polyclonal stimulus. T(regs) were identified by their expression of forkhead box protein 3 (FoxP3) and CD25 by direct staining of PBMCs. Although no changes were detected in the frequency of Th1 or Th17 cells, the percentages of peripheral T(regs) increased after therapy. In addition, the infrequent Th17/Th1 subpopulation showed a significant increment in tocilizumab-treated patients. In conclusion, tocilizumab was able to skew the balance between Th17 cells and T(regs) towards a more protective status, which may contribute to the clinical improvement observed in RA patients.

Figures

Figure 1
Figure 1
T helper type 1 (Th1), Th17 and Th17/Th1 populations in rheumatoid arthritis (RA) patients treated with tocilizumab. (a) Representative dot-plots of CD4+ T cells expressing interferon (IFN)-γ (Th1), IL-17 (Th17) and both cytokines simultaneously (Th17/Th1) after a polyclonal stimulus, in peripheral blood mononuclear cells (PBMCs) from a healthy control and an RA patient before and after 6 months of therapy. (b–d) Percentages of Th1 cells (b), Th17 cells (c) and Th17/Th1 cells (d) in PBMCs of RA patients at baseline and after 6 months of therapy. These populations were also determined in healthy controls (HC). Horizontal lines represent median values. **P < 0·01.
Figure 2
Figure 2
Regulatory T cells (Tregs) in rheumatoid arthritis (RA) patients treated with tocilizumab. (a) Representative dot-plots of CD4+ forkhead box protein 3 (FoxP3)+ Tregs from a healthy control and an RA patient before and after 6 months of therapy. (b) Representative histogram showing that the CD4+ FoxP3+ population expresses higher levels of CD25 than the CD4+ FoxP3 population. (c) Percentages of Tregs in the blood of healthy controls (HC) and RA patients at baseline and after 6 months of therapy with tocilizumab. (d) Treg/Th17 ratios on HC and on RA patients at baseline and after 6 months of therapy. Horizontal lines represent median values. **P < 0·01; ***P < 0·001.

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