Rheumatology Advance Access originally published online on January 6, 2004
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Rheumatology 2004; 43: 442-447
Rheumatology Vol. 43 No. 4 (c) British Society for Rheumatology 2004; all rights reserved
Basic Science |
Effect of neutralizing antibodies to IL-10 and C5 on the renal damage caused by a pathogenic human anti-dsDNA antibody*
Centre for Rheumatology, Department of Medicine, 1Department of Histopathology, University College London, Arthur Stanley House, London W1T 4NJ, 2Institute of Child Health, 30 Guildford Street, London WC1N 1EH, UK and 3Alexion Pharmaceutical Inc., Cheshire, CT, USA.
Correspondence to: D. A. Isenberg, Centre for Rheumatology, Department of Rheumatology, University College London, Arthur Stanley House, 40–50 Tottenham Street, London W1T 4NJ, UK. E-mail: d.isenberg{at}ucl.ac.uk
Objectives. There is considerable evidence suggesting that anti-double-stranded deoxyribonucleic acid (anti-dsDNA) antibodies are involved in the pathogenesis of lupus nephritis. It was shown previously using severe combined immune deficient (SCID) mice that when the hybridomas secreting human immunoglobulin G (IgG) anti-dsDNA antibodies, RH14 and DIL-6, were implanted intraperitoneally the antibodies produced by RH14, but not DIL-6, deposited in the kidneys, caused pathological changes in the renal tissues and induced proteinuria. In this study we have further analysed the effect of activated terminal complement proteins and interleukin-10 (IL-10) in the pathogenesis of glomerulonephritis caused by the RH-14.
Methods. SCID mice implanted with RH-14 or DIL-6 cell lines were treated with neutralizing antibodies to IL-10 (mAb B-S10) or anti-complement factor 5 (anti-C5) (mAb BB5.1) intraperitoneally. Control groups received either an isotype control antibody (135.8) or phosphate-buffered saline (PBS). Serum human IgG levels and proteinuria were estimated and the extent of renal involvement was examined by histopathological and electron microscopic techniques.
Results. While there was a tendency to reduce proteinuria in the anti-IL-10 injected group the anti-C5 injected group showed a significant reduction in proteinuria (P<0.01) compared with the groups injected with either the control mAb or PBS. There was a considerable reduction in the serum human IgG levels in the anti-IL-10 but not in the anti-C5 treated animals. Both anti-IL-10 and anti-C5 treated groups showed significantly reduced renal impairment as revealed by histopathological examination and proteinuria assessment.
Conclusion. The findings, while confirming the role of IL-10 and activated terminal complement component in the production of antibody at the cellular level and at the site of glomerular immune deposition in this model, respectively, also suggest the beneficial effect of a combined therapy using both anti-IL-10 and anti-C5 mAb to prevent or reduce the effect of the humoral immune response in lupus disease.
KEY WORDS: Systemic lupus erythematosus, Anti-DNA antibodies, Nephritis, IL-10, C5.
*This work was supported by the Arthritis and Rheumatism Council, UK.
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