Higher efficacy of anti-IL-6/IL-21 combination therapy compared to monotherapy in the induction phase of Th17-driven experimental arthritis.

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.

• Authors: Debbie M Roeleveld, Renoud J Marijnissen, Birgitte Walgreen, Monique M Helsen, Liduine van den Bersselaar, Fons A van de Loo, Peter L van Lent, Peter M van der Kraan, Wim B van den Berg, Marije I Koenders
• Journal: PloS one (PLoS One) Vol. 12 Issue 2 Pg. e0171757 ( 2017) ISSN: 1932-6203 [Electronic] United States
• PMID: 28158305 (Publication Type: Journal Article)

Chemical References

• Interleukin-6
• Interleukins
• Collagen
• interleukin-21

Topics

• Animals
• Arthritis, Experimental (chemically induced, drug therapy, metabolism)
• CD4-Positive T-Lymphocytes
• Cell Differentiation (drug effects)
• Collagen (toxicity)
• Female
• Flow Cytometry
• Interleukin-6 (therapeutic use)
• Interleukins (therapeutic use)
• Male
• Mice
• Signal Transduction (drug effects)
• Th17 Cells (metabolism)