Treatment with anti-C5aR mAb leads to early-onset clinical and mechanistic effects in the murine delayed-type hypersensitivity arthritis model.
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.
a Department of Immunopharmacology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark .|b Department of Veterinary Disease Biology, Section for Experimental Animal Models , University of Copenhagen , Frederiksberg , Denmark .
Sara M
SM
Atkinson
a Department of Immunopharmacology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark .
Anneline
A
Nansen
c Department of Histology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark .
Pernille A
PA
Usher
c Department of Histology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark .
Bodil-Cecilie
BC
Sondergaard
d School of Biomedical Sciences, Monash University , Clayton , Victoria , Australia .
Charles R
CR
Mackay
e Department of Mammalian Cell Technology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark , and.
Birgitte
B
Friedrichsen
f Department of Cell Biology , Novo Nordisk A/S, Beijing , China.
Chih-Chuan
CC
Chang
f Department of Cell Biology , Novo Nordisk A/S, Beijing , China.
Renhong
R
Tang
b Department of Veterinary Disease Biology, Section for Experimental Animal Models , University of Copenhagen , Frederiksberg , Denmark .
Søren
S
Skov
a Department of Immunopharmacology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark .
Claus
C
Haase
a Department of Immunopharmacology , Biopharmaceuticals Research Unit , Novo Nordisk A/S, Maaloev , Denmark .
Lars
L
Hornum
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D057134:Antibodies, Neutralizing / Q000494:pharmacology*; D000936:Antigen-Antibody Complex / Q000378:metabolism; D001169:Arthritis, Experimental / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D015936:Complement C5a / Q000037:antagonists & inhibitors / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D004487:Edema / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006614:Hindlimb; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D018655:Lymphocyte Count; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration / Q000187:drug effects; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000936:Antigen-Antibody Complex; D044087:Receptor, Anaphylatoxin C5a; D015936:Complement C5a
Bone erosion; C5a; complement; neutrophils; rheumatoid arthritis