Inhibition of complement factor C5 protects against anti-myeloperoxidase antibody-mediated glomerulonephritis in mice.
In mice, administration of murine anti-myeloperoxidase (MPO) IgG induces pauci-immune necrotizing crescentic glomerulonephritis. Recent studies in this model indicate a crucial role for complement activation in disease induction. Here, we investigated the effect of pretreatment or intervention with a C5-inhibiting monoclonal antibody (BB5.1) in the mouse model of anti-MPO IgG-induced glomerulonephritis. Mice received BB5.1 8 h before or 1 day after disease induction with anti-MPO IgG and lipopolysaccharide. Mice were killed after 1 or 7 days. Control antibody-pretreated mice developed hematuria, leukocyturia and albuminuria, and glomerulonephritis with a mean of 21.0+/-8.8% glomerular crescents and 12.8+/-5.5% glomerular capillary necrosis. BB5.1 pretreatment prevented disease development, as evidenced by the absence of urinary abnormalities, a marked reduction in glomerular neutrophil influx at day 1 and normal renal morphology at day 7. Importantly, BB5.1 administration 1 day after disease induction also resulted in a marked attenuation of urinary abnormalities and a more than 80% reduction in glomerular crescent formation. In conclusion, inhibition of C5 activation attenuates disease development in a mouse model of anti-MPO IgG-induced glomerulonephritis. These results favor further investigations into the role of complement activation in human MPO-anti-neutrophil cytoplasmic autoantibody-mediated glomerulonephritis, and indicate that inhibition of C5 activation is a potential therapeutic approach in this disease.
Huugen
D
D
Department of Clinical and Experimental Immunology, Cardiovascular Research Institute Maastricht, University Maastricht, Maastricht, The Netherlands.
van Esch
A
A
Xiao
H
H
Peutz-Kootstra
C J
CJ
Buurman
W A
WA
Tervaert
J W Cohen
JW
Jennette
J C
JC
Heeringa
P
P
D000818:Animals; D003182:Complement C5 / Q000037:antagonists & inhibitors*; D005921:Glomerulonephritis / Q000276:immunology* / Q000517:prevention & control; D007074:Immunoglobulin G / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D009195:Peroxidase / Q000276:immunology*
D003182:Complement C5; D007074:Immunoglobulin G; D009195:Peroxidase