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K J Assmann

Publications and source records attributed to K J Assmann.

At least 19 recordsLinked to original sources
PubMed1998

IL-4 is an endogenous inhibitor of neutrophil influx and subsequent pathology in acute antibody-mediated inflammation.

IL-4 is an immunoregulatory cytokine that has in vitro and in vivo anti-inflammatory actions. In this study we investigated whether endogenously produced IL-4 modulates inflammatory processes that occur after Abs bind to target tissue by comparing the severity of glomerulonephritis induced by heterologous anti-glomerular basement membrane Abs in wild-type (IL-4+/+) mice to that of glomerulonephritis induced in homozygous IL-4 gene knockout (IL-4-/-) mice. Two hours after Ab injection, IL-4-/- mice had significantly higher intrarenal intercellular adhesion molecule-1 mRNA expression and intraglomerular neutrophil accumulation than the IL-4+/+ group. Treatment of IL-4-/- mice with recombinant murine IL-4 at the time of disease induction reduced intercellular adhesion molecule-1 expression and neutrophil influx to levels observed in IL-4+/+ kidneys. Four days after Ab administration, untreated IL-4-/- mice developed significantly greater urinary protein excretion, intracapillary fibrinogen deposits, and glomerular hypercellularity than IL-4+/+ mice. These results demonstrate that endogenous IL-4 suppresses neutrophil influx and limits tissue damage in Ab-induced glomerulonephritis, suggesting that IL-4 is an important regulator of acute inflammatory processes.

Acute Disease↗
PubMed1998

Anti-GBM glomerulonephritis in mice lacking nitric oxide synthase type 2.

Nitric oxide is synthesized in experimental immune complex glomerulonephritis due to local induction of type 2 nitric oxide synthase (NOS2). To determine the role of NOS2, the course of accelerated anti-glomerular basement membrane glomerulonephritis (anti-GBM) was examined in mice homozygous for disruption of the NOS2 gene compared with heterozygous littermates. Disease in the wild type strain (129Sv) was characterized by heavy albuminuria, glomerular neutrophil and macrophage infiltration and glomerular thrombosis. NOS2, interleukin 1B (IL-1 beta) and tumor necrosis factor alpha (TNF alpha) mRNA were induced by 24 hours. The NOS2-deficient mutant mice and the heterozygous mice displayed early (24 hr) and full autologous phase (day 6) injury indistinguishable from the wild-type mice. The equivalent degree of albuminuria and glomerular inflammation indicates that NOS2 does not play an essential role in this form of glomerulonephritis in the mouse.

Animals↗
PubMed1998

Agrin is a major heparan sulfate proteoglycan in the human glomerular basement membrane.

Agrin is a heparan sulfate proteoglycan (HSPG) that is highly concentrated in the synaptic basal lamina at the neuromuscular junction (NMJ). Agrin-like immunoreactivity is also detected outside the NMJ. Here we show that agrin is a major HSPG component of the human glomerular basement membrane (GBM). This is in addition to perlecan, a previously characterized HSPG of basement membranes. Antibodies against agrin and against an unidentified GBM HSPG produced a strong staining of the GBM and the NMJ, different from that observed with anti-perlecan antibodies. In addition, anti-agrin antisera recognized purified GBM HSPG and competed with an anti-GBM HSPG monoclonal antibody in ELISA. Furthermore, both antibodies recognized a molecule that migrated in SDS-PAGE as a smear and had a molecular mass of approximately 200-210 kD after deglycosylation. In immunoelectron microscopy, agrin showed a linear distribution along the GBM and was present throughout the width of the GBM. This was again different from perlecan, which was exclusively present on the endothelial side of the GBM and was distributed in a nonlinear manner. Quantitative ELISA showed that, compared with perlecan, the agrin-like GBM HSPG showed a sixfold higher molarity in crude glomerular extract. These results show that agrin is a major component of the GBM, indicating that it may play a role in renal ultrafiltration and cell matrix interaction. (J Histochem Cytochem 46:19-27, 1998)

Adult↗
PubMed1998

Monocyte chemoattractant protein-1 and interleukin-8 levels in urine and serum of patents with hemolytic uremic syndrome.

The epidemic form of the hemolytic uremic syndrome (HUS) in children is hallmarked by endothelial cell damage, most predominantly displayed by the glomerular capillaries. The influx of mononuclear (MO) and polymorphonuclear cells (PMNs) into the glomeruli may be an important event in the initiation, prolongation, and progression of glomerular endothelial cell damage in HUS patients. The molecular mechanisms for the recruitment of these leukocytes into the kidney are unclear, but monocyte chemoattractant protein-1 (MCP-1) and IL-8 are suggested to be prime candidates. In this study, we analyzed the presence of both chemokines in 24-h urinary (n = 15) and serum (n = 14) samples of HUS children by specific ELISAs. Furthermore, kidney biopsies of three different HUS children were examined for MO and PMN cell infiltration by histochemical techniques and electron microscopy. Whereas the chemokines MCP-1 and IL-8 were present in only very limited amounts in urine of 17 normal control subjects, serial samples of HUS patients demonstrated significantly elevated levels of both chemokines. HUS children with anuria showed higher initial and maximum chemokine levels than their counterparts without anuria. A strong positive correlation was observed between urinary MCP-1 and IL-8 levels. Whereas initial serum IL-8 levels were significantly increased in HUS children, serum MCP-1 levels were only slightly elevated compared with serum MCP-1 in control children. No correlation was found between urinary and serum chemokine concentrations. Histologic and EM studies of HUS biopsy specimens clearly showed the presence of MOs and to a lesser extent of PMNs in the glomeruli. The present data suggest an important local role for MOs and PMNs in the process of glomerular endothelial-cell damage. The chemokines MCP-1 and IL-8 may possibly be implicated in the pathogenesis of HUS through the recruitment and activation of MOs and PMNs, respectively.

Biomarkers↗
PubMed1997

A role for Mac-1 (CDIIb/CD18) in immune complex-stimulated neutrophil function in vivo: Mac-1 deficiency abrogates sustained Fcgamma receptor-dependent neutrophil adhesion and complement-dependent proteinuria in acute glomerulonephritis.

Mac-1 (alphambeta2), a leukocyte adhesion receptor, has been shown in vitro to functionally interact with Fcgamma receptors to facilitate immune complex (IC)-stimulated polymorphonuclear neutrophil (PMN) functions. To investigate the relevance of Mac-1-FcgammaR interactions in IC-mediated injury in vivo, we induced a model of Fc-dependent anti-glomerular basement membrane (GBM) nephritis in wild-type and Mac-1-deficient mice by the intravenous injection of anti-GBM antibody. The initial glomerular PMN accumulation was equivalent in Mac-1 null and wild-type mice, but thereafter increased in wild-type and decreased in mutant mice. The absence of Mac-1 interactions with obvious ligands, intercellular adhesion molecule 1 (ICAM-1), and C3 complement, is not responsible for the decrease in neutrophil accumulation in Mac-1- deficient mice since glomerular PMN accumulation in mice deficient in these ligands was comparable to those in wild-type mice. In vitro studies showed that spreading of Mac-1-null PMNs to IC-coated dishes was equivalent to that of wild-type PMNs at 5-12 min but was markedly reduced thereafter, and was associated with an inability of mutant neutrophils to redistribute filamentous actin. This suggests that in vivo, Mac-1 is not required for the initiation of Fc-mediated PMN recruitment but that Mac-1-FcgammaR interactions are required for filamentous actin reorganization leading to sustained PMN adhesion, and this represents the first demonstration of the relevance of Mac-1-FcgammaR interactions in vivo. PMN-dependent proteinuria, maximal in wild-type mice at 8 h, was absent in Mac-1 mutant mice at all time points. Complement C3-deficient mice also had significantly decreased proteinuria compared to wild-type mice. Since Mac-1 on PMNs is the principal ligand for ic3b, an absence of Mac-1 interaction with C3 probably contributed to the abrogation of proteinuria in Mac-1-null mice.

Actins↗
PubMed1997

[Glomerulonephritis caused by acute serum sickness].

A 51-year-old male patient was treated for a rejection episode after kidney transplantation with horse antithymocyte globulin (ATG). Twelve days after the start of the ATG treatment he developed fever, arthralgia, purpura and acute renal failure. This clinical picture is characteristic of serum sickness, resulting from formation of antibodies to a foreign protein and development of immune complexes. Kidney biopsy revealed an endocapillary glomerulonephritis. Immune complexes probably develop in the mesangium and along the glomerular basal membrane through local formation and precipitation from the circulation. Spontaneous recovery is the rule.

Acute Disease↗
PubMed1997

Evidence for the existence of multiple heparan sulfate proteoglycans in the human glomerular basement membrane and mesangial matrix.

Heparan sulfate proteoglycans (HSPGs) are essential components of the glomerular basement membrane (GBM) carrying a strong anionic charge. A well-characterized extracellular HSPG is perlecan, ubiquitously expressed in basement membranes. A cDNA construct encoding domains I and II of human perlecan was expressed as a fusion protein with glutathione S-transferase. This fusion protein was used to generate monoclonal antibody 95J10. We compared the staining pattern of 95J10 with that of M215, a previously prepared mAb that recognizes HSPG isolated from human GBM. In kidney cortex, the anti-perlecan mAb 95J10 showed a strong staining of the mesangium, Bowman's capsule, the tubular basement membrane, and stained the GBM only slightly. In contrast, M215 predominantly stained the GBM in a linear fashion. Immunoelectron microscopy supported these results, showing concentrations of perlecan in some regions of the GBM, whereas the unidentified M215 antigen was homogenously distributed throughout the GBM. In other human tissues, both antibodies also produced a different staining pattern. Furthermore, a polyclonal antiserum recognizing HSPG isolated from the GBM did not recognize perlecan from EHS tumors. These results provide evidence for the presence of another HSPG in the GBM that is immunologically distinct from perlecan. The absence of perlecan splice variants in the kidney suggests that this component is encoded by a different gene than perlecan. Given its marked expression in the GBM, this component could be a determining factor in the maintenance of selective glomerular permeability.

Animals↗
PubMed1997

Recurrence of type I membranoproliferative glomerulonephritis after renal transplantation: analysis of the incidence, risk factors, and impact on graft survival.

BACKGROUND: The information in the medical literature on the incidence of recurrence of type I membranoproliferative glomerulonephritis (MPGN) after renal transplantation and its impact on graft survival is limited because most data are derived from case reports or from studies involving a small number of patients. METHODS: We analyzed the data from our transplant center. Among 1097 adult patients receiving their first allograft between 1977 and 1994, we identified 32 patients with type I MPGN. RESULTS: A recurrence was detected in 9 of the 27 recipients of a first cadaveric graft (33%). The cumulative incidence reached 48% at 4 years after transplantation when patients with graft failure from other causes were censored. All patients with recurrent MPGN had clinically significant proteinuria (>1 g/24 hr) that was first observed at a median time of 20 months (range, 1.5-42 months) after transplantation. Graft survival was significantly worse in patients with recurrence as compared with patients without recurrence. Mean duration of graft survival after the diagnosis of recurrence was 40 months. We could not detect any clinical characteristics of patients or donors that were associated with recurrent disease. However, an increased risk of recurrence was observed in patients with the HLA haplotype B8DR3. Four patients received an HLA-identical graft from a living related donor. Recurrence occurred in three patients (75%), with ensuing graft loss in two. The only patient with a haploidentical living related graft did not have a recurrence. Five patients with a recurrence in the first graft received a second transplant. Recurrence was observed in four of these patients (80%). CONCLUSIONS: Type I MPGN recurred after renal transplantation in half of the patients. The incidence may be even higher in recipients of an identical living related donor graft and in patients receiving a second transplant after having experienced a recurrence in their first graft. Recurrence of type I MPGN has a detrimental effect on graft survival.

Adult↗
PubMed1997

Effects of TNF alpha on verocytotoxin cytotoxicity in purified human glomerular microvascular endothelial cells.

In the pathogenesis of the hemolytic uremic syndrome (HUS), endothelial damage of glomeruli and arterioles of the kidney appears to play a central role. Previous studies have shown that verocytotoxin-1 (VT-1) cytotoxicity on human vein endothelial cells require additional stimuli, in particular the inflammatory mediator tumor necrosis factor alpha (TNF alpha). In this study the effects of VT on human glomerular microvascular endothelial cells (GMVEC) were examined. A reproducible method was developed for the isolation and purification of large numbers of highly purified GMVEC. The obtained GMVEC were over 99% pure; their endothelial origin was demonstrated by the expression of the endothelial antigens von Willebrand factor, EN-4, PECAM-1 and V,E-cadherin. Upon stimulation with TNF alpha the cells expressed the endothelial-specific adhesion molecule E-selectin. A limited number of fenestral structures was observed by scanning electron microscopy (SEM), suggesting glomerular origin of the endothelial cells. Cytotoxicity of VT-1 to GMVEC was evaluated by determination of the number of viable adherent cells and by assay of overall protein synthesis after exposure to varying concentrations of VT-1. In non-stimulated GMVEC, cytotoxicity of VT-1 was inversely related to the degree and duration of confluence, subconfluent cells being the most sensitive. In highly confluent GMVEC, VT cytotoxicity required pre-exposure of the cells to the inflammatory mediator TNF alpha, which induced an increase in the number of VT receptors on GMVEC. Thin layer chromatography of extracted glycolipids from the GMVEC showed binding of VT-1 to globotriaosylceramide (Gb3), known to be the functional receptor for VT. There were no major differences in protein synthesis inhibition with equal concentrations VT-1 and VT-2. In conclusion, in this study we provide a reproducible method to isolate, purify and culture well characterized human GMVEC on a routine basis. In vitro studies with these GMVEC demonstrate that VT cytotoxicity depends on the degree of confluence and the additional preexposure to the inflammatory mediator TNF alpha. These observations provide further insight into the complex events that may occur in glomeruli in the pathogenesis of HUS.

Bacterial Toxins↗
PubMed1997

Overexpression of aminopeptidase A abolishes the growth promoting effects of angiotensin II in cultured mouse mesangial cells.

Angiotensin II (Ang II) has diverse effects on the glomerular tuft such as regulation of glomerular hemodynamics and stimulation of mesangial cell growth, and may be one pivotal factor in the progression of renal disease. In order to locally inactivate Ang II, we overexpressed aminopeptidase A (E.C. 3.4.11.7; ATA), a peptidase involved in the conversion of Ang II into angiotensin III, in a mouse mesangial cell line (MMC) that normally does not exhibit this enzyme. Stable transfections were selected in medium containing G418. ATA-overexpressing clones ATA5 and ATA21 revealed mRNA, protein, and enzyme activity in contrast to wild-type MMCs or mock-transfected Neo3 cells (stably transfected with expression vectors without ATA cDNA). There was no difference in the binding of Ang II to its putative receptors in all cell lines. Ang II increased intracellular inositol 1,4,5-triphosphate (IP3) in Neo3, but not in ATA5 and ATA21 cells. In contrast to MMCs and Neo3 cells, Ang II failed to stimulate proliferation in ATA5 and ATA21 clones as measured by [3H] thymidine incorporation and direct cell counts. However, ATA5 and ATA21 revealed a mitogenic response not different from MMCs after stimulation 2% or 10% of fetal calf serum. Treatment of ATA5 and ATA21 with 0.1 mM of the ATA-inhibitor amastatin or an ATA-inhibiting specific monoclonal antibody restored the proliferative effect of Ang II, suggesting that surface activity of ATA is involved in the attenuated mitogenesis in these cell. Our study demonstrates that it is feasible to overexpress Ang II-degrading enzymes in cultured mesangial cells and that this overexpression attenuated some effect of exogenous Ang II. These experiments are a first step toward the development of novel strategies to selectively antagonize locally generated Ang II in the kidney.

Aminopeptidases↗
PubMed1997

Nucleosomes and histones are present in glomerular deposits in human lupus nephritis.

BACKGROUND: Recently we showed that antinuclear autoantibodies complexed to nucleosomes can bind to heparan sulphate (HS) in the glomerular basement membrane (GBM) via the histone part of the nucleosome. Histones have been identified in glomerular deposits in human and murine lupus nephritis. In addition, a decreased HS staining in the GBM was found, most probably due to masking by deposition of antibodies complexed to nucleosomes. METHODS: In this study we first investigated whether histones or nucleosomes could be identified in glomerular deposits in human lupus nephritis, and secondly whether the presence of these nuclear components was correlated with absence of HS staining. Kidney biopsies of SLE patients (11 with diffuse proliferative glomerulonephritis (DPGN) and six with membranous glomerulonephritis (MGN)) and non-SLE glomerular diseases were stained for histones. DNA, nucleosomes, IgG and HS. RESULTS: Using a polyclonal anti-H3 1 21 antiserum, histones were detected in all patients with DPGN and in two of six patients with SLE-MGN (P < 0.01). Using a monoclonal antihistone antibody, histones were stained in three patients with DPGN, but in none of the biopsies with MGN. Using nucleosome specific monoclonal antibodies, nucleosomes were detected in five patients with DPGN, in two patients with MGN, but in none of the biopsies with non-SLE glomerulonephritis. HS staining was nearly absent in DPGN, whereas staining was only moderately reduced in patients with MGN and controls (P = 0.001). CONCLUSION: Using polyclonal and monoclonal antihistone antisera, histones were identified in all patients with DPGN and their presence was associated with a decrease of HS staining. Nucleosomes were identified in five of 11 patients with DPGN and in two of six patients with MGN. This is the first demonstration of nucleosomes in glomerular deposits in SLE nephritis.

Adolescent↗
PubMed1997

Mouse glomerular epithelial cells in culture with features of podocytes in vivo express aminopeptidase A and angiotensinogen but not other components of the renin-angiotensin system.

The binding of antibodies to podocytic antigens such as the Heymann antigen or aminopeptidase A may lead to the induction of a membranous glomerulonephritis in several species. To study the possible future interactions of antibodies with antigens on these podocytes, epithelial cells from isolated mouse glomeruli were cultured. By indirect immunofluorescence, the cells were positive for cytokeratin, vimentin, desmin, and the ZO-1 protein, a component of the tight junction complex. When rat monoclonal antibodies were used, the cells were also positive for the hydrolases aminopeptidase A and dipeptidyl peptidase IV, and they stained with ASD-33, a monoclonal antibody that recognized an epitope only present on the cell membranes of mouse podocytes. They were negative for the von Willebrand factor and did not stain with a monoclonal antibody (ASD-13) that binds to endothelial cells of glomeruli and peritubular capillaries. By electron microscopy, the cells showed tight junctions but lacked Weibel Palade bodies (endothelium), desmosomes, and cilia (parietal epithelium). The mRNA expression of several components of the renin-angiotensin system was also examined, and some factors indirectly coupled to the renin-angiotensin system component angiotensin II in this podocytic culture by RT-PCR analysis. mRNA Expression for the angiotensin II degrading hydrolase aminopeptidase A and angiotensinogen was found, but this was not found for any other component of this system, such as renin, angiotensin-converting enzyme, or the angiotensin II receptors AT1a, AT1b, and AT2. Low mRNA expression for dipeptidyl peptidase IV was observed. In addition, expression of the growth factors transforming growth factor-beta and interleukin-7, and the extracellular matrix components fibronectin, laminin B2, perlecan, and collagen IV alpha 1, was observed. Given these characteristics, a glomerular epithelial cell culture with features of podocytes in vivo that will allow future studies on the interaction of anti-aminopeptidase A monoclonal antibodies and angiotensin II with aminopeptidase A was established. This is of interest in light of the observation that injection of mice with anti-aminopeptidase A antibodies causes an acute albuminuria.

Aminopeptidases↗
PubMed1996

N-Acetylated domains in heparan sulfates revealed by a monoclonal antibody against the Escherichia coli K5 capsular polysaccharide. Distribution of the cognate epitope in normal human kidney and transplant kidney with chronic vascular rejection.

The Escherichia coli K5 capsular polysaccharide has the same (GlcUA-->GlcNAc)n structure as the nonsulfated heparan sulfate/heparin precursor polysaccharide. A monoclonal antibody (mAb 865) against the K5 polysaccharide has been described (Peters, H., Jürs, M., Jann, B., Jann, K., Timmis, K. N., and Bitter-Sauermann, D. (1985) Infect. Immun. 50, 459-466). In this report, we demonstrate the binding of anti-K5 mAb 865 to N-acetylated sequences in heparan sulfates and heparan sulfate proteoglycans but not to heparin. This is shown by direct binding and fluid phase inhibition of mAb 865 in an enzyme-linked immunosorbent assay. In this system we found that the binding of the mAb decreased with increasing sulfate content of the polysaccharide. By testing chemically modified K5 and heparin polysaccharides, we found that each of the modifications that occur during heparan sulfate (HS) synthesis (N-sulfation, C-5 epimerization, and O-sulfation) prevents recognition by mAb 865. Samples of heparan sulfate from human aorta (HS-II) were selectively degraded so as to allow the separate isolation of N-sulfated and N-acetylated block structures. N-Sulfated oligosaccharides (obtained after N-deacetylation by hydrazinolysis followed by nitrous acid deamination at pH 3.9) were not recognized by mAb 865, in contrast to N-acetylated oligosaccharides (obtained after nitrous acid deamination at pH 1.5), although the reactivity was lower than for intact HS-II. Analysis of the latter's pH 1.5 deamination products by gel filtration indicated that a minimal size of 18 saccharide units was necessary for antibody binding. These results lead us to propose bivalent antibody-heparan sulfate interaction, in which both F(ab) domains of the mAb interact with their epitopes, both of which are present in a single large (>/=18 saccharide units) N-acetylated domain and additionally with single epitopes present in two N-acetylated sequences (each <18 saccharide units) bridged by a short N-sulfated domain. Immunohistochemistry with mAb 865 on cryostat sections of normal human kidney tissue, revealed its binding to most but not all renal basement membranes. However, all renal basement membranes contain heparan sulfate, as shown by a mAb against heparitinase-digested heparan sulfate stubs (mAb 3G10). This finding indicates that not all heparan sulfate chains present in basement membranes express the mAb 865 epitopes. Besides the normal distribution, mAb 865 staining was found in fibrotic and sclerotic lesions in vessels, interstitium, and mesangium in transplant kidneys with chronic vascular rejection. Occasionally, a decrease of staining was observed within tubulo-interstitium and glomeruli. These findings show that N-acetylated sequences in heparan sulfates can be demonstrated by anti-K5 mAb 865 in normal and diseased kidneys.

Acetylation↗
PubMed1996

Acute passive anti-glomerular basement membrane nephritis in P-selectin-deficient mice.

P-selectin present on surfaces of activated endothelium and platelets mediates neutrophil-endothelial and neutrophilplatelet interactions. The role of P-selectin in vivo was examined in a model of acute passive anti-GBM nephritis in P-selectin-deficient and wild-type mice which was induced by intravenous injection of anti-GBM serum. There were two major differences between P-selectin-deficient and wild-type mice. Firstly, mutant mice had approximately two fold more glomerular PMNs and albuminuria than wild-type animals at the peak of neutrophil influx and proteinuria. Secondly, Lipoxin A4 (LXA4), an eicosanoid which inhibits leukocyte-endothelial adhesion in vitro, and is generated primarily by transcellular biosynthetic routes during P-selectin-mediated platelet-PMN interaction [1], was approximately 60% of wild type levels in nephritic kidneys of P-selectin-deficient mice. Injection of wild-type platelets into P-selectin-null mice restored LXA4 to wild-type levels. The corresponding PMN influx approximated PMN levels in wild-type mice receiving platelets but urine albuminuria remained higher. Although these two P-selectin-dependent events cannot be directly linked, our results point to the importance of considering both platelet and endothelial P-selectin in determining the cellular events in inflammation.

Acute Disease↗
PubMed1996

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 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.

Animals↗