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FRI0005 Combination Blocking of IL-22 and IL-17 During Experimental Arthritis Potently Reduces TH17-Driven Disease Progression
  1. D.M. Roeleveld,
  2. R. Rogier,
  3. B. Walgreen,
  4. M.M. Helsen,
  5. L. van den Bersselaar,
  6. W.B. van den Berg,
  7. P.M. van der Kraan,
  8. M.I. Koenders
  1. Experimental Rheumatology, Radboud umc, Nijmegen, Netherlands

Abstract

Background Rheumatoid arthritis (RA) patients show elevated levels of IL-22 and IL-22-producing T helper cells that correlate to erosive disease, suggesting a role for this cytokine in the pathogenesis of RA. Interestingly, IL-22 is a dual cytokine with pro- and anti-inflammatory properties, and its effects might be regulated by cooperation and crosstalk with IL-17.

Objectives The purpose of this study was to elucidate the role of IL-22 in the development of a spontaneous model of experimental arthritis by using IL-1Ra knockout mice. Additionally, we aimed to investigate the therapeutic potential of combined IL-22/IL-17 blocking during experimental arthritis.

Methods IL-1Ra-deficient mice develop spontaneous arthritis due to excess IL-1 signaling, and we previously demonstrated the importance of IL-17 and Th17 cells in this model1. To investigate the role of IL-22 in this arthritis model, we compared IL-1Ra-/- x IL-22+/+ mice to IL-1Ra-/- mice lacking IL-22 expression. Paw joint swelling was scored weekly, and mice were sacrificed at the age of fifteen weeks. In addition, arthritic IL-1Ra-/- x IL-22-/- mice were treated with anti-IL-17 antibodies to determine the therapeutic potency of this combined blocking strategy during experimental arthritis.

Results IL-1Ra-/- mice that also lack IL-22 showed strongly reduced arthritis development, reaching a disease incidence of only 54% at the age of 15 weeks compared to 93% in IL-1Ra-/- x IL-22+/+ mice. In addition, arthritis severity of the mice that did develop arthritis was significantly reduced by 30.6% in the absence of IL-22. Interestingly, combined blocking of IL-22 and IL-17 using IL-1Ra-/- x IL-22-/- mice treated with neutralizing anti-IL-17 antibodies after the onset of arthritis demonstrated clear additive effects compared to blocking these single cytokines alone, thereby potently reducing progression of this Th17-driven arthritis model.

Conclusions These findings suggest that IL-22 plays an important role both in the initiation and augmentation of Th17-dependent experimental arthritis, and that targeting IL-22, especially in combination with IL-17 therefore seems an interesting, potent strategy in RA treatment.

References

  1. Koenders MI, Devesa I, Marijnissen RJ, Abdollahi-Roodsaz S, Boots AM, Walgreen B, di Padova FE, Nicklin MJ, Joosten LA, van den Berg WB. Interleukin-1 drives pathogenic Th17 cells during spontaneous arthritis in interleuking-1 receptor antagonist-deficient mice. Arthritis Rheum. 58(11): 3461-70, 2008.

Disclosure of Interest None declared

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