Date: Sunday, October 21, 2018
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.
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 August 3, 2020.
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ACR Meeting Abstracts - 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/