A3.5 Combination Blocking of IL-6 and IL-21 in Experimental Arthritis Inhibits their Redundant Role in Th17-Driven Joint Pathology
Authors: Marije I Koenders, Debbie M Roeleveld, Renoud J Marijnissen, Cheryl Nickerson-Nutter, Fons van de Loo, Wim B van den Berg
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background and Objectives</h3> Both IL-6 and IL-21 have been described to drive in vitro Th17 differentiation in the presence of TGFbeta. We explored whether also in vivo IL-6 and IL-21 play an exchangeable and redundant role in Th17 differentiation during experimental arthritis, and to what extent combined blocking of these cytokines inhibits Th17 differentiation and suppresses arthritis development. <h3>Materials and Methods</h3> To investigate the synergistic effects of combined blocking of the IL-6 and IL-21 pathways, arthritis development and Th17 cells were first studied in IL-6<sup> -/-</sup>xIL-21R<sup>-/-</sup> mice and their wild-type (WT) and single-knockout controls during antigen-induced arthritis (AIA). In addition, the kinetic effects of combined IL-6R and IL-21 neutralisation was studied in DBA-1J mice treated at various stages of collagen-induced arthritis (CIA). <h3>Results</h3> Mice deficient for either IL-6 or IL-21R showed suppressed antigen-induced arthritis compared to WT controls. This disease reduction was accompanied by a significant reduction in CD4+IL17+ T cells in the draining lymph nodes as determined by FACS. However, mice lacking both the IL-6 and IL-21 signalling pathways showed an even stronger disease suppression than the IL-6<sup>-/-</sup> and IL-21R<sup>-/-</sup> mice, and a striking reduction in Th17 levels was observed in these mice. Based upon our findings in gene-knockout mice, we aimed to confirm the synergistic effects of IL-6/IL-21 with a cytokine-neutralisation approach using anti-IL-6R antibodies and sIL-21R-Fc treatment during CIA. Antibodies were given as single treatment or in combination, and was started at immunisation (day 0) or around the booster (day 21). Combined blocking of IL-6R and IL-21 early during arthritis development (day 0) was a very potent approach to prevent arthritis development, reaching a disease incidence of only 40% at day 35 (isotype control 100%, sIL-21R-Fc 100%, anti-IL-6R 60%). Analyzing the mice that did develop arthritis, we observed that the anti-IL-6R/sIL-21R-Fc combination was also clearly more potent in suppressing the arthritis severity in comparison to the single treatments. Interestingly, blocking the IL-6/IL-21 pathways at a later stage during arthritis development (day 21) was clearly less effective and did not show any additional effects to anti-IL-6R treatment alone. <h3>Conclusions</h3> Combined blocking of the IL-6 and IL-21 pathways suppresses Th17 differentiation in vivo as demonstrated by our IL-6/IL-21R-deficient mice. However, our neutralisation study during CIA shows that to influence arthritis development this IL-6/IL-21 blocking approach only has a limited therapeutic window. These findings suggests that to target Th17-driven joint pathology, blocking Th17 effector cytokines like IL-17 and IL-22 might be more effective than attempting to reduce Th17 cell numbers during active disease.