Prevention of C5 activation ameliorates spontaneous and experimental glomerulonephritis in factor H-deficient mice

Proceedings of the National Academy of Sciences of the United States of America - Tập 103 Số 25 - Trang 9649-9654 - 2006
Matthew C. Pickering1, Joanna Warren2, Kamala Rose2, Francesco Carlucci2, Y. Wang3, Mark Walport4, H. Terence Cook5, Marina Botto2
1Rheumatology Section and Department of Histopathology, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom.
2*Rheumatology Section and
3Alexion Pharmaceuticals Inc., 352 Knotter Drive, Cheshire, CT 80410; and
4The Wellcome Trust, 215 Euston Road, London NW1 2BE, United Kingdom
5Department of Histopathology, Faculty of Medicine, Imperial College, Hammersmith Campus, Du Cane Road, London W12 0NN, United Kingdom;

Tóm tắt

Membranoproliferative glomerulonephritis (MPGN) type II (dense deposit disease) is an inflammatory renal disease characterized by electron-dense deposits and complement C3 on the glomerular basement membrane. There is no effective therapy. We investigated the role of C5 activation in a model of MPGN that develops spontaneously in complement factor H-deficient mice (Cfh−/−). At 12 months there was a significant reduction in mortality, glomerular cellularity, neutrophil numbers, and serum creatinine levels inCfh−/−mice deficient in C5. Excessive glomerular neutrophil numbers, frequently seen in patients with MPGN during disease flares, were also observed inCfh−/−mice after the administration of an antiglomerular basement membrane antibody. This exaggerated injurious phenotype was absent inCfh−/−mice deficient in C5 but not inCfh−/−mice deficient in C6, indicating a key role for C5 activation in the induction of renal lesions. Importantly, the renal injury was completely reversed inCfh−/−mice pretreated with an anti-murine C5 antibody. These results demonstrate an important role for C5 in both spontaneous MPGN and experimentally induced nephritis in factor H-deficient mice and provide preliminary evidence that C5 inhibition therapy might be useful in human MPGN type II.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 103 Số 25

9649-9654

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