Complement has both protective and pathogenic functions in lupus due to a balance between its role in the clearance of immune complexes (IC’s) and apoptotic cells versus inflammation. The classical pathway contributes to IC and apoptotic cell clearance, whereas the alternative pathway is a key mediator of renal inflammation. We investigated the effect of a new targeted inhibitor of the alternative pathway, CR2-fH, on lupus-like renal disease in MRL/lpr mice.
Mice were treated with either saline, CR2-fH, CR2-Crry (inhibits all complement pathways) or sCR2 (C3d-binding targeting vehicle). Sera were analyzed every 2 weeks for autoantibodies, circulating ICs and C3. Urinary albumin was also determined, and kidneys collected for histological evaluation at 23 weeks.
CR2-fH and CR2-Crry treatment improved survival and significantly reduced proteinuria, glomerular C3 deposition and circulating IC’s. CR2-fH, but not CR2-Crry, also significantly reduced glomerulonephritis, serum anti-dsDNA antibodiesa, and glomerular IgG and C1q deposition. Interestingly, sCR2 also significantly reduced levels of anti-dsDNA antibodies, circulating IC’s and glomerular deposition of IgG, C1q and C3, although there was no significant reduction in glomerulonephritis, proteinuria or mortality.
Targeted and selective inhibition of the alternative complement pathway is an effective treatment for murine lupus, and is more effective than blockade of all pathways. The data demonstrate benefits to leaving the classical/lectin pathways intact, and indicate distinct roles for the classical and alternative pathways of complement in progression of the disease. The sCR2 targeting vehicle contributes to therapeutic activity, possibly via modulation of autoimmunity.