Amelioration of lupus-like autoimmune disease in NZB/WF1 mice after treatment with a blocking monoclonal antibody specific for complement component C5.

TLDR

NZB/WF1 mice spontaneously develop a lupus‑like syndrome with high antinuclear antibodies and fatal glomerulonephritis by 12 months, accompanied by complement activation whose pathogenic role remains unclear. The study aimed to determine whether activated terminal complement proteins drive disease progression. Female NZB/WF1 mice received a C5‑specific monoclonal antibody that blocks C5 cleavage, thereby preventing generation of C5a and the membrane attack complex. Six‑month anti‑C5 treatment markedly reduced glomerulonephritis, improved survival, and confirmed the terminal complement cascade’s pivotal role, indicating C5 inhibition as a potential therapy for immune‑complex glomerulonephritis.

Abstract

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.