Objectives Randomised-controlled trials have recently proven the efficacy of the interleukin (IL)-6 receptor antagonist tocilizumab (TCZ) in giant cell arteritis (GCA). However, the mechanism of action of IL-6 blockade in this disease is unknown. Moreover, the role of regulatory T (Treg) cells in the pathogenesis of GCA remains underexplored. Given the plasticity of Tregs and the importance of IL-6 in their biology, we hypothesised that TCZ might modulate the Treg response in GCA. We therefore characterised the Treg compartment of patients with GCA treated with TCZ.
Methods We classified 41 patients with GCA into three groups: active disease (aGCA, n=11), disease remission on corticosteroids (rGCA-CS, n=19) and disease remission on TCZ (rGCA-TCZ, n=11). Healthy controls (HCs) were included for comparison. We determined the frequency, phenotype and function of peripheral blood Tregs.
Results Patients with aGCA demonstrated a hypoproliferating Treg compartment enriched in IL-17-secreting Tregs (IL-17+Tregs). Tregs in patients with aGCA disproportionally expressed a hypofunctional isoform of Foxp3 that lacks exon 2 (Foxp3Δ2). Foxp3Δ2-expressing Tregs coexpressed CD161, a marker commonly associated with the Th17 linage, significantly more often than full-length Foxp3-expressing Tregs. Compared with those of HCs, GCA-derived Tregs demonstrated impaired suppressor capacity. Treatment with TCZ, in contrast to CS therapy, corrected the Treg abnormalities observed in aGCA. In addition, TCZ treatment increased the numbers of activated Tregs (CD45RA−Foxp3high) and the Treg expression of markers of trafficking (CCR4) and terminal differentiation (CTLA-4).
Conclusions TCZ may exert its therapeutic effects in GCA by increasing the proliferation and activation of Tregs, and by reverting the pathogenic Treg phenotype seen during active disease.
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Handling editor Tore K Kvien
ADL and SU contributed equally.
Correction notice This article has been corrected since it published Epub ahead of print. The fifth sentence of the introduction has been amended and co-author details have been updated.
Contributors Substantial contributions to the conception or design of the work, or the acquisition, analysis or interpretation of data: CM, YM, KS, NDK, JHS, ADL and SU; drafting the work or revising it critically for important intellectual content: CM, YM, KS, NDK, JHS, ADL and SU; final approval of the version published: CM, YM, KS, NDK, JHS, ADL and SU; agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved: ADL and SU.
Funding Arthritis Foundation CRTA grant #5924, Japan Heart Foundation and Bayer Yakuhin Research Grant Abroad.
Competing interests None declared.
Patient consent Obtained.
Ethics approval This protocol was approved by the Partners Human Research Committee. Institutional board review (IRB) protocol 2012P002348/MGH.
Provenance and peer review Not commissioned; externally peer reviewed.
Data sharing statement All data related with this study are presented in the revised manuscript and online supplementary material.
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