title: The dual role of complement in the progression of renal disease in NZB/W F(1) mice and alternative pathway inhibition.
abstract: Complement plays a dual role in the progression of systemic lupus erythematosus since it has important protective functions, such as the clearance of immune complexes and apoptotic cells, but is also a mediator of renal inflammation. To investigate this balance in a clinically relevant setting, we investigated how targeted inhibition of all complement pathways vs. targeted inhibition of only the alternative pathway impacts immune and therapeutic outcomes in NZB/W F(1) mice. Following onset of proteinuria, mice were injected twice weekly with CR2-fH (inhibits alternative pathway), CR2-Crry (inhibits all pathways at C3 activation step), sCR2 (C3d targeting vehicle) or saline. Sera were analyzed every 2 weeks for anti-dsDNA antibody levels, and urinary albumin excretion was determined. Kidneys were collected for histological evaluation at 32 weeks. Compared to the control group, all CR2-fH, CR2-Crry and sCR2 treated groups showed significantly reduced serum anti-dsDNA antibody levels and strong trends towards reduced glomerular IgG deposition levels. Glomerular C3 deposition levels were also significantly reduced in all three-treated groups. However, significant reductions of disease activity (albuminuria and glomerulonephritis) were only seen in the CR2-fH treated group. These data highlight the dual role played by complement in the pathogenesis of lupus, and demonstrate a benefit of selectively inhibiting the alternative complement pathway, presumably because of protective contributions from the classical and/or lectin pathways. The sCR2 targeting moiety appears to be contributing to therapeutic outcome via modulation of autoimmunity. Furthermore, these results are largely consistent with our previous data using the MRL/lpr lupus model, thus broadening the significance of these findings.
authors: Department of Medicine, Division of Rheumatology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA.
authors: Hideharu
authors: H
authors: Sekine
authors: Phillip
authors: P
authors: Ruiz
authors: Gary S
authors: GS
authors: Gilkeson
authors: Stephen
authors: S
authors: Tomlinson
mesh_terms: D000419:Albuminuria / Q000276:immunology; D000818:Animals; D003170:Complement Pathway, Alternative / Q000276:immunology*; D003171:Complement Pathway, Classical / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D008181:Lupus Nephritis / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008814:Mice, Inbred NZB