HEPARIN AND HEPARINOIDS PREVENT THE BINDING OF IMMUNE-COMPLEXES CONTAINING NUCLEOSOMAL ANTIGENS TO THE GBM AND DELAY NEPHRITIS IN MRL LPR MICE/

Monoclonal anti-nucleosome antibodies (mAbs) complexed to nucleosomal antigens can bind to DNA and to heparan sulfate (HS) in ELISA and to t he GEM in vivo in a rat renal perfusion system, whereas non-complexed mAbs do not bind [1]. In this study, we analyzed whether heparin (HEP) or N-desulfated/acetylated heparins (DSA-HEP), structurally and funct ionally strongly related to HS, are able to prevent the binding of the se complexed mAbs to DNA and to HS in vitro and to rat GEM in vivo. In ELISA the binding of nucleosome complexed anti-nucleosome antibodies to DNA and HS was inhibited dose-dependently by HEP, DSA-HEP and low m olecular weight (LMW) DSA-HEP. Intravenous injection of nucleosome/ant i-nucleosome immune complexes without heparin/heparinoids in BALB/c mi ce led to GEM binding, while simultaneous injection of heparin/heparin oids with complexed antibodies or pretreatment with heparin subcutaneo usly prior to injection of complexes prevented this binding. Subsequen tly, we tested the preventive effect of HEP, DSA-HEP and LMW-DSA-HEP o n progression of renal disease in MRL/lpr mice. Treatment was started at an age of eight weeks in a dose of 50 mu g daily. With all three dr ugs albuminuria was significantly delayed compared to PBS treated cont rols (cumulative incidence of proteinuria at 20 weeks in controls 60% vs. 13%, 14% and 6% respectively for HEP, DSA-HEP and LMW-DSA-HEP; P < 0.05). At week 21 the glomerulonephritis was histologically less seve re in heparin/heparinoid treated animals (P = 0.02). In immunofluoresc ence the amount of immunoglobulin and C3 deposits in the glomerular ca pillary wail tended to be less in heparin/heparinoid treated mice comp ared to PBS treated controls (P = 0.07). Furthermore, at 20 weeks anti -HS levels in plasma of heparin/heparinoid treated mice were significa ntly lower (P < 0.05). We conclude that interaction of heparin or hepa rin analogs with HS reactive immune complexes containing nucleosomal a ntigens prevents the binding of these immune complexes to the GEM and delays nephritis in MRL/lpr mice.