Prevention and reversal of nephritis in MRL/lpr mice with a single injection of C‐reactive protein

Abstract

Objective C‐reactive protein (CRP) is an acute‐phase serum protein with binding reactivity to nuclear autoantigens and immunomodulatory function. The MRL/lpr mouse is an important model of human systemic lupus erythematosus (SLE). These mice develop high‐titer anti‐DNA antibodies and immune complex–mediated nephritis and exhibit progressive lymphadenopathy. The mortality rate among these mice is 50% by age 18–20 weeks; the most frequent cause of death is glomerulonephritis. The present study was undertaken to determine whether treatment of mice with CRP would affect the course of lupus nephritis. Methods MRL/lpr mice were treated with a single 200‐μg injection of CRP at either age 6 weeks (before disease onset) or age 13 or 15 weeks (when proteinuria had reached high levels). Proteinuria was measured weekly, and levels of anti–double‐stranded DNA autoantibodies and blood urea nitrogen were determined monthly. Glomerular immune complex deposition and renal pathology were assessed in mice ages 15 weeks and 17 weeks. Results Early CRP treatment markedly delayed the onset of proteinuria and lymphadenopathy, increased survival, and reduced levels of autoantibodies to DNA. Treatment of mice with active disease reversed proteinuria and prolonged survival. Renal disease was decreased in CRP‐treated mice, with a marked suppression of glomerular pathology, tubular degeneration, and interstitial inflammation, which correlated with the decrease in proteinuria and azotemia. Conclusion These findings demonstrate that systemic suppression of autoimmunity is initiated by a single injection of CRP. Long‐term maintenance of CRP‐mediated protection was reversed by injection of an anti‐CD25 monoclonal antibody but not by macrophage depletion, suggesting that disease suppression is maintained by CD25‐bearing T cells.