Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model

Abstract

Blockade of the complement cascade at the C5a/C5a receptor (C5aR)-axis is believed to be an attractive treatment avenue in rheumatoid arthritis (RA). However, the effects of such interventions during the early phases of arthritis remain to be clarified. In this study we use the murine delayed-type hypersensitivity arthritis (DTHA) model to study the very early effects of a blocking, non-depleting anti-C5aR mAb on joint inflammation with treatment synchronised with disease onset, an approach not previously described. The DTHA model is a single-paw inflammatory arthritis model characterised by synchronised and rapid disease onset driven by T-cells, immune complexes and neutrophils. We show that a reduction in paw swelling, bone erosion, cartilage destruction, synovitis and new bone formation is apparent as little as 60 h after administration of a single dose of a blocking, non-depleting anti-mouse C5aR mAb. Importantly, infiltration of neutrophils into the joint and synovium is also reduced following a single dose, demonstrating that C5aR signalling during the early stage of arthritis regulates neutrophil infiltration and activation. Furthermore, the number of T-cells in circulation and in the draining popliteal lymph node is also reduced following a single dose of anti-C5aR, suggesting that modulation of the C5a/C5aR axis results in effects on the T cell compartment in inflammatory arthritis. In summary, these data demonstrate that blockade of C5aR leads to rapid and significant effects on arthritic disease development in a DTHA model strengthening the rationale of C5aR-blockade as a treatment strategy for RA, especially during the early stages of arthritis flare.

• Bone erosion
• C5a
• complement
• neutrophils
• rheumatoid arthritis

Acknowledgements

The authors sincerely thank Kirstine Smedenfors, Mie Berndorff, Julie Jensen, Malik Nygaard Nielsen, Jette Mandelbaum, Pia Rothe, and Birthe Jørgensen for excellent technical assistance, Josephine Hebsgaard for coordinating the histopathology processing and evaluation, and the staff of Laboratory Animal Science, Novo Nordisk A/S, Maaloev for taking care of the animals and assisting with blood sampling.

Declaration of interest

Anneline Nansen, Pernille Autzen Usher, Bodil-Cecilie Søndergaard, Birgitte Friedrichsen, Chih-Chuan Chang, Claus Haase and Lars Hornum are employees of Novo Nordisk A/S and minor shareholders in the company. The study was funded in full by Novo Nordisk A/S, except the salary of Sara Marie Atkinson, which was funded by the Novo Nordisk LIFE In Vivo Pharmacology Centre (LIFEPHARM) at the University of Copenhagen.

Supplementary material available online Supplementary Figure S1