Higher efficacy of anti-IL-6/IL-21 combination therapy compared to monotherapy in the induction phase of Th17-driven experimental arthritis.
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.
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Debbie M
http://orcid.org/0000-0002-5414-3299
DM
Roeleveld
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Renoud J
RJ
Marijnissen
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Birgitte
B
Walgreen
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Monique M
MM
Helsen
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Liduine
L
van den Bersselaar
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Fons A
FA
van de Loo
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Peter L
PL
van Lent
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Peter M
PM
van der Kraan
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Wim B
WB
van den Berg
Department of Experimental Rheumatology, Radboud University Medical Center, Nijmegen, the Netherlands.
Marije I
MI
Koenders
D000818:Animals; D001169:Arthritis, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes; D002454:Cell Differentiation / Q000187:drug effects; D003094:Collagen / Q000633:toxicity*; D005260:Female; D005434:Flow Cytometry; D015850:Interleukin-6 / Q000627:therapeutic use*; D007378:Interleukins / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D015398:Signal Transduction / Q000187:drug effects; D058504:Th17 Cells / Q000378:metabolism*; D000098546:Interleukin-21
D015850:Interleukin-6; D007378:Interleukins; D003094:Collagen; D000098546:Interleukin-21