Administration of a soluble recombinant complement C3 inhibitor protects against renal disease in MRL/lpr mice

• Published in: Journal of the American Society of Nephrology Vol. 14; no. 3; pp. 670 - 679
• Main Authors: BAD, Lihua, HAAS, Mark, KRAUS, Damian M, HACK, Bradley K, RAKSTANG, Jonathan K, HOLERS, V. Michael, QUIGG, Richard J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD Lippincott Williams & Wilkins 01-03-2003
• Subjects: Albuminuria - drug therapy; Albuminuria - pathology; Animals; Autoimmunity - immunology; Biological and medical sciences; Complement C3 - antagonists & inhibitors; Complement Inactivator Proteins - pharmacology; Dermatitis - immunology; Disease Models, Animal; Immunoglobulin G - pharmacology; Lupus Nephritis - drug therapy; Lupus Nephritis - pathology; Lupus Nephritis - prevention & control; Male; Medical sciences; Mice; Mice, Inbred MRL lpr; Pharmacology. Drug treatments; Recombinant Proteins - pharmacology; Renal Insufficiency - prevention & control; Solubility; Urinary system; Vasculitis - immunology; Glomerulonephritis; Skin disease; Complement C3; Autoimmune disease; Prevention; Systemic disease; Complication; Lupus erythematosus; Disseminated; Recombinant protein; Kidney disease; Immunopathology; Connective tissue disease; Urinary system disease; Treatment efficiency; Rodentia; Pathology; Vertebrata; Chemotherapy; Mammalia; Treatment; Mouse; Animal; Renal failure; Inhibitor
• ISSN: 1046-6673; 1533-3450
• DOI: 10.1097/01.asn.0000051597.27127.a1

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.