Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5.
New Zealand black x New Zealand white (NZB/W) F1 mice spontaneously develop an autoimmune syndrome with notable similarities to human systemic lupus erythematosus. Female NZB/WF1 mice produce high titers of antinuclear antibodies and invariably succumb to severe glomerulonephritis by 12 months of age. Although the development of the immune-complex nephritis is accompanied by abundant local and systemic complement activation, the role of proinflammatory complement components in disease progression has not been established. In this study we have examined the contribution of activated terminal complement proteins to the pathogenesis of the lupus-like autoimmune disease. Female NZB/W F1 mice were treated with a monoclonal antibody (mAb) specific for the C5 component of complement that blocks the cleavage of C5 and thus prevents the generation of the potent proinflammatory factors C5a and C5b-9. Continuous therapy with anti-C5 mAb for 6 months resulted in significant amelioration of the course of glomerulonephritis and in markedly increased survival. These findings demonstrate an important role for the terminal complement cascade in the progression of renal disease in NZB/W F1 mice, and suggest that mAb-mediated C5 inhibition may be a useful approach to the therapy of immune-complex glomerulonephritis in humans.
Wang
Y
Y
Immunobiology Program, Alexion Pharmaceuticals, Inc., New Haven, CT 06511, USA.
Hu
Q
Q
Madri
J A
JA
Rollins
S A
SA
Chodera
A
A
Matis
L A
LA
D000818:Animals; D019138:Antibodies, Blocking / Q000627:therapeutic use*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000936:Antigen-Antibody Complex; D001183:Arthus Reaction; D003167:Complement Activation; D003182:Complement C5 / Q000037:antagonists & inhibitors / Q000276:immunology*; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology / Q000628:therapy; D006579:Heterozygote; D007105:Immune Complex Diseases / Q000276:immunology / Q000628:therapy; D007167:Immunotherapy; D007668:Kidney / Q000473:pathology; D008180:Lupus Erythematosus, Systemic / Q000628:therapy*; D051379:Mice; D008814:Mice, Inbred NZB
D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000936:Antigen-Antibody Complex; D003182:Complement C5