1,25(OH)2D3 and Dexamethasone Additively Suppress Synovial Fibroblast Activation By CCR6+ T-Helper Memory Cells and Enhance the Effect of Tnfα Blockade

W Dankers¹, C González-Leal¹, N Davelaar², P Asmawidjaja³, A Otten-Mus², JMW Hazes⁴, E Colin⁵ and Erik Lubberts⁶, ¹Rheumatology, Erasmus MC, Rotterdam, Netherlands, ²Rheumatology and Immunology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ³Rheumatology, Erasmus MC, University Medical Center, Rotterdam, Netherlands, ⁴Erasmus Medical Centre, Rotterdam, Netherlands, ⁵ZGT Almelo, Deventer, Netherlands, ⁶Erasmus Medical Center, Rheumatology, Rotterdam, Netherlands

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: dexamethasone, fibroblasts and rheumatoid arthritis (RA), T cells, Vitamin D

Session Information

Date: Sunday, October 21, 2018

Session Title: T Cell Biology and Targets in Autoimmune and Inflammatory Disease Poster

Session Type: ACR Poster Session A

Session Time: 9:00AM-11:00AM

Background/Purpose: Despite improvement in treatment of rheumatoid arthritis (RA) over the past decades, insufficient treatment response and treatment resistance in many patients demonstrate the need to develop new therapeutic strategies. Chronic synovial inflammation could be suppressed by targeting activation of RA synovial fibroblasts (RASF) by for example IL-17A-producing CCR6+ T helper memory (memTh) cells. Previously, we have shown that dexamethasone (DEX) combined with the active vitamin D metabolite 1,25(OH)2D3 reduces pathogenicity of memTh cells. Therefore, we here studied the additive effect of 1,25(OH)2D3 and DEX on suppressing the pro-inflammatory loop between RASF and CCR6+ memTh cells and explored potential therapeutic applications.

Methods: CCR6+ memTh cells from PBMC of healthy donors or treatment-naïve early RA patients were cultured alone or with RASF from established RA patients for three days and treated with or without 1,25(OH)₂D₃, DEX or etanercept. Treatment effects were assessed using ELISA and flow cytometry.

Results: CCR6+ memTh produces less of the pro-inflammatory cytokines IL-17A, IL-22 and IFNγ upon exposure to 1,25(OH)₂D₃, and to a lesser extent by DEX. TNFα was only inhibited by the combination of 1,25(OH)₂D₃ and DEX. In contrast, in RASF cultures DEX was the strongest inhibitor of IL-6, IL-8 and tissue-destructive enzymes. As a result, 1,25(OH)₂D₃ and DEX additively inhibited inflammatory mediators in CCR6+ memTh-RASF co-cultures. Interestingly, low doses of mainly DEX, but also 1,25(OH)₂D₃, combined with etanercept better suppressed synovial inflammation in this co-culture model compared to etanercept alone.

Conclusion: This study suggests that 1,25(OH)₂D₃ and DEX additively inhibit synovial inflammation through targeting different pro-inflammatory mechanisms. Furthermore, low doses of DEX and 1,25(OH)₂D₃ enhance the effect of TNFα blockade in inhibiting RASF activation, providing a basis to improve RA treatment.

Disclosure: W. Dankers, None; C. González-Leal, None; N. Davelaar, None; P. Asmawidjaja, None; A. Otten-Mus, None; J. Hazes, None; E. Colin, None; E. Lubberts, None.

To cite this abstract in AMA style:

Dankers W, González-Leal C, Davelaar N, Asmawidjaja P, Otten-Mus A, Hazes J, Colin E, Lubberts E. 1,25(OH)2D3 and Dexamethasone Additively Suppress Synovial Fibroblast Activation By CCR6+ T-Helper Memory Cells and Enhance the Effect of Tnfα Blockade [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/125oh2d3-and-dexamethasone-additively-suppress-synovial-fibroblast-activation-by-ccr6-t-helper-memory-cells-and-enhance-the-effect-of-tnf%ce%b1-blockade/. Accessed January 27, 2021.

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