1. Kidney Int. 1996 Nov;50(5):1555-64.
Heparin and heparinoids prevent the binding of immune complexes containing nucleosomal antigens to the GBM and delay nephritis in MRL/lpr mice（题目） van Bruggen MC, Walgreen B, Rijke TP, Corsius MJ, Assmann KJ, Smeenk RJ, van
Dedem GW, Kramers K, Berden JH.
Department of Pathology, University Hospital Nijmegen, The Netherlands.
Monoclonal anti-nucleosome antibodies (mAbs) complexed to nucleosomal antigens
can bind to DNA and to heparan sulfate (HS) in ELISA and to the GBM 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 functionally strongly related to HS, are able to
prevent the binding of these complexed mAbs to DNA and to HS in vitro and to rat
GBM in vivo. In ELISA the binding of nucleosome complexed antinucleosome
antibodies to DNA and HS was inhibited dose-dependently by HEP, DSA-HEP and low
molecular weight (LMW) DSA-HEP. Intravenous injection of
nucleosome/anti-nucleosome immune complexes without heparin/heparinoids in BALB/c
mice led to GBM binding, while simultaneous injection of heparin/heparinoids with
complexed antibodies or pretreatment with heparin subcutaneously prior to
injection of complexes prevented this binding. Subsequently, we tested the
preventive effect of HEP, DSA-HEP and LMW-DSA-HEP on progression of renal disease
in MRL/lpr mice. Treatment was started at an age of eight weeks in a dose of 50
micrograms daily. With all three drugs albuminuria was significantly delayed
compared to PBS treated controls (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
severe in heparin/heparinoid treated animals (P = 0.02). In immunofluorescence
the amount of immunoglobulin and C3 deposits in the glomerular capillary wall
tended to be less in heparin/heparinoid treated mice compared to PBS treated
controls (P = 0.07). Furthermore, at 20 weeks anti-HS levels in plasma of
heparin/heparinoid treated mice were significantly lower (P < 0.05). We conclude
that interaction of heparin or heparin analogs with HS reactive immune complexes
containing nucleosomal antigens prevents the binding of these immune complexes to
the GBM and delays nephritis in MRL/lpr mice.
PMID: 8914022 [PubMed - indexed for MEDLINE]
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