Abstract
Th17 cells and their cytokines are linked to the pathogenesis of rheumatoid arthritis, a chronic autoimmune disease characterized by joint inflammation. Th17 development is initiated by combined signaling of TGF-β and IL-6 or IL-21, and can be reduced in the absence of either IL-6 or IL-21. The aim of this study was to assess whether combinatorial IL-6/IL-21 blockade would more potently inhibit Th17 development, and be more efficacious in treating arthritis than targeting either cytokine. We assessed in vitro Th17 differentiation efficacy in the absence of IL-6 and/or IL-21. To investigate in vivo effects of IL-6/IL-21 blockade on Th17 and arthritis development, antigen-induced arthritis (AIA) was induced in IL-6-/- x IL-21R-/- mice. The therapeutic potential of this combined blocking strategy was assessed by treating mice with collagen-induced arthritis (CIA) with anti-IL-6R antibodies and soluble (s)IL-21R.Fc. We demonstrated that combined IL-6/IL-21 blocking synergistically reduced in vitro Th17 differentiation. In mice with AIA, absence of IL-6 and IL-21 signaling more strongly reduced Th17 levels and resulted in stronger suppression of arthritis than the absence of either cytokine. Additionally, anti-IL-6/anti-IL-21 treatment of CIA mice during the arthritis induction phase reduced disease development more potent than IL-6 or IL-21 inhibition alone, as effective as anti-TNF treatment. Collectively, these results suggest dual IL-6/IL-21 inhibition may be a more efficacious therapeutic strategy compared to single cytokine blockade to suppress arthritis development.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects up to 1% of the population worldwide
Without IL-6, naïve T cells reached only 46% of Th17 development upon stimulation, while Th17 differentiation efficacy of naïve IL-21R-/- T cells was similar to that observed after stimulation of Wild type (WT) cells (Fig 1A and 1B)
When both IL6 and IL-21 signaling pathways were absent, only 17% of CD4+ cells differentiated into Th17 cells after culturing (Fig 1A and 1B), and IL-17 secretion was reduced by 50% (Fig 1C)
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease that affects up to 1% of the population worldwide. It is characterized by chronic inflammation leading to destruction of bone and cartilage of synovial joints [1]. The use of biologicals blocking a specific pathogenic target considerably improved symptoms and prognosis of some RA patients, PLOS ONE | DOI:10.1371/journal.pone.0171757. The use of biologicals blocking a specific pathogenic target considerably improved symptoms and prognosis of some RA patients, PLOS ONE | DOI:10.1371/journal.pone.0171757 February 3, 2017
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