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

J Am Soc Nephrol. 2003 Mar;14(3):670-9. doi: 10.1097/01.asn.0000051597.27127.a1.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Albuminuria / drug therapy
  • Albuminuria / pathology
  • Animals
  • Autoimmunity / immunology
  • 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
  • Mice
  • Mice, Inbred MRL lpr
  • Recombinant Proteins / pharmacology
  • Renal Insufficiency / prevention & control
  • Solubility
  • Vasculitis / immunology

Substances

  • Complement C3
  • Complement Inactivator Proteins
  • Immunoglobulin G
  • Recombinant Proteins