Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice.
Complement receptor 1-related gene/protein y (Crry) in rodents is a potent membrane complement regulator that inhibits complement C3 activation by both classical and alternative pathways. To clarify the role of complement in lupus nephritis, MRL/lpr mice were given Crry as a recombinant protein (Crry-Ig) from 12 to 24 wk of age. Control groups were given saline or normal mouse IgG. Sera and urine were collected biweekly. Only 1 of 20 (5%) Crry-Ig-treated mice developed renal failure (BUN > 50 mg/dl) compared with 18 of 38 (47.4%) mice in control groups (P = 0.001). BUN levels at 24 wk were reduced from 68.8 +/- 9.7 mg/dl in control groups to 38.5 +/- 3.9 mg/dl in the Crry-Ig-treated group (P < 0.01). Urinary albumin excretion at 24 wk was also significantly reduced from 5.3 +/- 1.4 mg/mg creatinine in the control groups to 0.5 +/- 0.2 mg/mg creatinine in the Crry-Ig-treated group (P < 0.05). Of the histologic data at 24 wk, there was a significant reduction in scores for glomerulosclerosis and C3d, IgG, IgG3, and IgA staining intensity in glomeruli in complement-inhibited animals. Crry-Ig-treated animals were also protected from vasculitic lesions. Although there was no effect on relevant autoimmune manifestations such as anti-double stranded DNA titers or cryoglobulin IgG3 levels, circulating immune complex levels were markedly higher in complement-inhibited animals. Thus, inhibition of complement activation with Crry-Ig significantly reduces renal disease in MRL/lpr lupus mice. The data support the strategy of using recombinant complement C3 inhibitors to treat human lupus nephritis.
Bao
Lihua
L
Section of Nephrology, The University of Chicago, Illinois 60637, USA.
Haas
Mark
M
Kraus
Damian M
DM
Hack
Bradley K
BK
Rakstang
Jonathan K
JK
Holers
V Michael
VM
Quigg
Richard J
RJ
D000419:Albuminuria / Q000188:drug therapy / Q000473:pathology; D000818:Animals; D015551:Autoimmunity / Q000276:immunology; D003176:Complement C3 / Q000037:antagonists & inhibitors*; D003169:Complement Inactivator Proteins / Q000494:pharmacology*; D003872:Dermatitis / Q000276:immunology; D004195:Disease Models, Animal; D007074:Immunoglobulin G / Q000494:pharmacology; D008181:Lupus Nephritis / Q000188:drug therapy* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D011994:Recombinant Proteins / Q000494:pharmacology; D051437:Renal Insufficiency / Q000517:prevention & control; D012995:Solubility; D014657:Vasculitis / Q000276:immunology
D003176:Complement C3; D003169:Complement Inactivator Proteins; D007074:Immunoglobulin G; D011994:Recombinant Proteins