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J Kuiper

Publications and source records attributed to J Kuiper.

At least 19 recordsLinked to original sources
PubMed2006

Induction of oral tolerance to oxidized low-density lipoprotein ameliorates atherosclerosis.

BACKGROUND: Oxidation of low-density lipoprotein (LDL) and the subsequent processing of oxidized LDL (oxLDL) by macrophages results in activation of specific T cells, which contributes to the development of atherosclerosis. Oral tolerance induction and the subsequent activation of regulatory T cells may be an adequate therapy for the treatment of atherosclerosis. METHODS AND RESULTS: Tolerance to oxLDL and malondialdehyde-treated LDL (MDA-LDL) was induced in LDL receptor-/- mice fed a Western-type diet by oral administration of oxLDL or MDA-LDL before the induction of atherogenesis. Oral tolerance to oxLDL resulted in a significant attenuation of the initiation (30% to 71%; P<0.05) and progression (45%; P<0.05) of atherogenesis. Tolerance to oxLDL induced a significant increase in CD4+ CD25+ Foxp3+ cells in spleen and mesenteric lymph nodes, and these cells specifically responded to oxLDL with increased transforming growth factor-beta production. Tolerance to oxLDL also increased the mRNA expression of Foxp3, CTLA-4, and CD25 in the plaque. In contrast, tolerance to MDA-LDL did not affect atherogenesis. CONCLUSIONS: OxLDL-specific T cells, present in LDL receptor-/- mice and important contributors in the immune response leading to atherosclerotic plaque, can be counteracted by oxLDL-specific CD4+ CD25+ Foxp3+ regulatory T cells activated via oral tolerance induction to oxLDL. We conclude that the induction of oral tolerance to oxLDL may be a promising strategy to modulate the immune response during atherogenesis and a new way to treat atherosclerosis.

Administration, Oral↗
PubMed2006

Genome-wide expression studies of atherosclerosis: critical issues in methodology, analysis, interpretation of transcriptomics data.

During the past 6 years, gene expression profiling of atherosclerosis has been used to identify genes and pathways relevant in vascular (patho)physiology. This review discusses some critical issues in the methodology, analysis, and interpretation of the data of gene expression studies that have made use of vascular specimens from animal models and humans. Analysis of gene expression studies has evolved toward the genome-wide expression profiling of large series of individual samples of well-characterized donors. Despite the advances in statistical and bioinformatical analysis of expression data sets, studies have not yet fully exploited the potential of gene expression data sets to obtain novel insights into the molecular mechanisms underlying atherosclerosis. To assess the potential of published expression data, we compared the data of a CC chemokine gene cluster between 18 murine and human gene expression profiling articles. Our analysis revealed that an adequate comparison is mainly hindered by the incompleteness of available data sets. The challenge for future vascular genomic profiling studies will be to further improve the experimental design, statistical, and bioinformatical analysis and to make data sets freely accessible.

Animals↗
PubMed2005

Delivery of Chlamydia pneumoniae to the vessel wall aggravates atherosclerosis in LDLr-/- mice.

OBJECTIVE: The role of Chlamydia pneumoniae in atherosclerosis is still debated. In this study a novel mouse model was applied to determine the direct impact of C. pneumoniae on the arterial wall and the development of atherosclerosis. METHODS: Direct effects of C. pneumoniae on collar-induced atherosclerosis were studied after local delivery of C. pneumoniae to carotid arteries of LDL receptor-deficient (LDLr-/-) mice. RESULTS: The presence of C. pneumoniae in the vessel wall was quantified by RT-PCR (6.2 x 10(4) copies/artery) and resulted in a 2.0-fold increase in intima/media ratios (p<0.05) and a 1.7-fold increase in stenosis (p<0.05). Immunostaining revealed a 2.98-fold (p<0.01) increased macrophage content and a tendency towards lower numbers of smooth muscle cells and collagen in lesions of infected carotid arteries. Direct delivery of another respiratory pathogen, Mycoplasma pneumoniae, to the carotids did not affect size or composition of the atherosclerotic lesions. Presence of C. pneumoniae in the carotid arteries resulted within 7 days in a marked upregulation of the expression of MCP-1 (p<0.01) and ICAM-1 as determined on mRNA and protein levels. These in vivo data were in line with data obtained with in vitro infections of macrophages and endothelial cells with C. pneumoniae. CONCLUSIONS: We conclude that C. pneumoniae in carotid arteries leads to more pronounced atherosclerotic lesions with a more vulnerable morphology and that this model is suitable to monitor direct effects of C. pneumoniae on atherogenesis.

Animals↗
PubMed2005

Blockade of interleukin-12 function by protein vaccination attenuates atherosclerosis.

BACKGROUND: Interleukin-12 (IL-12) has been identified as a key inducer of a type 1 T-helper cell cytokine pattern, which is thought to contribute to the development of atherosclerosis. We sought to study the role of IL-12 in atherosclerosis by inhibition of IL-12 using a newly developed vaccination technique that fully blocks the action of IL-12. METHODS AND RESULTS: LDL receptor-deficient (LDLr(-/-)) mice were vaccinated against IL-12 by 5 intramuscular injections of IL-12-PADRE complex in combination with adjuvant oil-in-water emulsion (low dose)/MPL/QS21 every 2 weeks. Two weeks thereafter, atherogenesis was initiated in the carotid artery by perivascular placement of silicone elastomer collars. IL-12 vaccination resulted in the induction of anti-IL-12 antibodies that functionally blocked the action of IL-12 as determined in an IL-12 bioassay. Blockade of IL-12 by vaccination of LDLr(-/-) mice resulted in significantly reduced (68.5%; P<0.01) atherogenesis compared with control mice without a change in serum cholesterol levels. IL-12 vaccination also resulted in a significant decrease in intima/media ratios (66.7%; P<0.01) and in the degree of stenosis (57.8%; P<0.01). On IL-12 vaccination, smooth muscle cell and collagen content in the neointima increased 2.8-fold (P<0.01) and 4.2-fold (P<0.01), respectively. CONCLUSIONS: Functional blockade of endogenous IL-12 by vaccination resulted in a significant 68.5% reduction in atherogenesis in LDLr(-/-) mice. Vaccination against IL-12 also improved plaque stability, from which we conclude that the blockade of IL-12 by vaccination may be considered a promising new strategy in the treatment of atherosclerosis.

Animals↗
PubMed2004

Overexpression of IL-18 decreases intimal collagen content and promotes a vulnerable plaque phenotype in apolipoprotein-E-deficient mice.

OBJECTIVE: Although IL-18 has been implicated in atherosclerotic lesion development, little is known about its role in advanced atherosclerotic plaques. This study aims to assess the effect of IL-18 overexpression on the stability of preexisting plaques. METHODS AND RESULTS: Atherosclerotic lesions were elicited in carotid arteries of apolipoprotein E (apoE)-deficient mice (n=32) by placement of a perivascular collar. Overexpression of IL-18 was effected by intravenous injection of an adenoviral vector 5 weeks after surgery. Two weeks after transduction, lesions were analyzed histologically with regard to plaque morphology and composition or by real-time polymerase chain reaction. No difference in plaque size was detected between groups. In the Ad.IL-18-treated group, 62% of lesions displayed a vulnerable morphology or even intraplaque hemorrhage as compared with only 24% in the controls (P=0.037). In agreement, IL-18 overexpression reduced intimal collagen by 44% (P<0.003) and cap-to-core ratio by 41% (P<0.002). Although IL-18 did not affect the expression of collagen synthesis-related genes, it was found to enhance the collagenolytic activity of vascular smooth muscle cells in vitro, suggesting that the low collagen content is attributable to matrix degradation rather than to decreased synthesis. CONCLUSIONS: Systemic IL-18 overexpression markedly decreases intimal collagen content and cap thickness, leading to a vulnerable plaque morphology.

Animals↗
PubMed2003

Identification of an internalising peptide in differentiated Calu-3 cells by phage display technology; application to gene delivery to the airways.

Differentiated, human submucosal-gland carcinoma, Calu-3 cell monolayers were used as in vitro model for the airway epithelium. Internalised phage were selected from a recombinant pComb8 phage library by repetitive cycles of bio-panning on Calu-3 monolayers, protease K degradation, cell-lysis and amplification. After four selection rounds, sequence analysis of 15 enriched phage colonies revealed two clones of 73 and 27% abundancy, named IB1 and IB2, respectively. The IB2 sequence was eliminated due to a frame shift. IB1-phage internalisation at 4 degrees C was significantly lower (P < 0.05) than at 37 degrees C, suggesting involvement of a receptor-mediated endocytosis pathway. The IB1 peptide was synthesised, biotinylated and complexed to streptavidin. IB1/streptavidin-complexes co-administrated with PEI/DNA-polyplexes, enhanced polyplex transfection efficiency, dose dependently, by 6- and 4-fold in Calu-3 cells. IB1/Alexa488-streptavidin complexes were used for confocal laser-scanning microscopy (CLSM) visualisation and showed basolateral localisation in membrane associated and internalising vesicles. This study demonstrates the potential of phage display technology for identification of internalising peptide-epitopes that can enhance gene delivery efficiency in differentiated airway epithelial cells.

Biotin↗
PubMed2002

Characterization of the binding of urokinase-type plasminogen activator to the asialoglycoprotein receptor.

In order to study the role of the asialoglycoprotein receptor (ASGPr) in the rapid plasma clearance of urokinase-type plasminogen activator (u-PA), a microtiter plate binding assay was developed using ASGPr purified from rat liver extracts. Urinary two-chain u-PA bound to immobilized ASGPr in a saturable manner with an EC50 of 0.2 microM. Binding was inhibited by rabbit antibodies against the ASGPr. In line with the known carbohydrate specificity of the ASGPr, GalNAc proved to be the most effective inhibitor from a series of monosaccharides, followed by Gal and Fuc, whereas GlcNAc was ineffective. The N-linked oligosaccharides of urinary u-PA do not terminate with the common Gal-GlcNAc element, but with a GalNAc-GlcNAc element which is partially sulfated. Sulfated forms of u-PA were separated from non-sulfated forms by using the lectin Wisteria floribunda agglutinin. Only the non-sulfated forms of u-PA (30% of the total) appeared to bind to the ASGPr. From different u-PA preparations used for thrombolytic therapy only urinary u-PA and u-PA produced by kidney cell cultures strongly bound to the ASGPr, whereas (recombinant) u-PA expressed in mouse myeloma cells, Chinese hamster ovary cells or E. coli scarcely bound to the receptor. It is concluded that u-PA bearing non-sulfated GalNAc-GlcNAc elements is specifically recognized by the ASGPr present on liver cells.

Acetylgalactosamine↗
PubMed2001

Attenuation of atherogenesis by systemic and local adenovirus-mediated gene transfer of interleukin-10 in LDLr-/- mice.

In view of its multifaceted anti-inflammatory properties, interleukin-10 (IL-10) has been deemed to be potentially anti-atherogenic. We have evaluated the capacity of adenoviral gene transfer of IL-10 for the modulation of de novo atherosclerotic lesion formation by systemic and by local overexpression. Atherogenesis was initiated in the carotid arteries of low-density lipoprotein receptor deficient mice by perivascular placement of silastic collars. One week after collar placement, mice were injected intravenously with 1 x 109 plaque-forming units (pfu's) of IL-10 (AdV.IL-10) or control adenovirus (AdV.empty). Administration of AdV.IL-10 resulted in extended systemic expression of IL-10 (peak serum level 3.0 +/- 1.1 ng/ml) and a reduction in atherosclerotic lumen stenosis by 62.2% (P<0.02). This finding was accompanied by monocyte deactivation and lowering of serum cholesterol levels (maximum decrease 44%). In a second experiment, collared arteries were transfected locally by transluminal instillation of adenovirus (titer 1.5x1010 pfu/ml). Systemic parameters remained unchanged following local transfection, but the degree of stenosis was, nonetheless, decreased by 44.9% (P<0.05). We conclude that a marked inhibition of atherogenesis can be achieved by systemic overexpression of AdV.IL-10, owing to its metabolic and immunomodulatory effects. Local IL-10 transfer is virtually equipotent, however, and it may represent a valuable addition to the armory of anti-atherosclerotic therapies.

Adenoviridae↗
PubMed2001

Recombinant lipoproteins: lipoprotein-like lipid particles for drug targeting.

Lipoproteins are endogenous particles that transport lipids through the blood to various cell types, where they are recognised and taken up via specific receptors. These particles are, therefore, excellent candidates for the targeted delivery of drugs to various tissues. For example, the remnant receptor and the asialoglycoprotein receptor (ASGPr), which are uniquely localised on hepatocytes, recognise chylomicrons and lactosylated high density lipopoteins (HDL), respectively. In addition, tumour cells of various origins overexpress the low density lipoprotein (LDL) receptor that recognises apolipoprotein E (apoE) on small triglyceride-rich particles and apoB-100 on LDL. Being endogenous, lipoproteins are biodegradable, do not trigger immune reactions, and are not recognised by the reticuloendothelial system (RES). However, their endogenous nature also hampers large-scale pharmaceutical application. In the past two decades, various research groups have successfully synthesised recombinant lipoproteins from commercially available natural and synthetic lipids and serum-derived or recombinant apolipoproteins, which closely mimic the metabolic behaviour of their native counterparts in animal models as well as humans. In this paper, we will summarise the studies that led to the development of these recombinant lipoproteins, and we will address the possibility of using these lipidic particles to selectively deliver a wide range of lipophilic, amphiphilic, and polyanionic compounds to hepatocytes and tumour cells. In addition, the intrinsic therapeutic activities of recombinant chylomicrons and HDL in sepsis and atherosclerosis will be discussed.

Animals↗
PubMed2001

A structure-function study of ligand recognition by CD22beta.

B-cell-specific CD22 is a member of a group of cell adhesion molecules within the immunoglobulin superfamily that display binding to glycans with terminal sialic acid residues. Binding of endogenous ligands to CD22 triggers B-cell activation and proliferation. It is therefore conceivable that high affinity ligands for CD22 may be of value as inhibitors of B-cell activation in allergy and chronic inflammation. In this study, we aimed to delineate the structural requirements for ligand binding to CD22. A library of 20 mono-, di-, and trisaccharide analogs of the basic binding motif Neu5Ac(alpha2,6)Lac was synthesized and screened for affinity for CD22beta. In general, CD22 ligand recognition appeared to be rather tolerant with respect to structural modifications of the anomeric sugar on a mono-, di-, and trisaccharide level, although affinity was increased by the presence of a nitro aromatic group at C-2. The most potent monovalent ligand, Neu5Ac-4-nitrobenzoyl-Glc, was selected to generate multivalent ligands based on either a glutamate or Tris cluster core. All multivalent ligands displayed at least a 10-fold increased affinity for CD22 compared with the corresponding monovalent glycoside. Interestingly, a maximal gain in affinity was already obtained for bivalent ligands, regardless of the terminal glycoside. A trivalent Tris-based cluster of Neu5Ac-4-nitrobenzoyl-Glc displayed a 300-fold higher affinity compared with the basic binding motif, which makes it, to our knowledge, the most potent antagonist for CD22 yet synthesized. As our in vitro fluorescence-activated cell sorting studies demonstrated efficient cellular uptake of a CD22 substrate, the most potent ligand in this study may hold promise as a homing device for immunomodulatory compounds and cytostatics.

Animals↗
PubMed2001

Apolipoprotein E protects against bacterial lipopolysaccharide-induced lethality. A new therapeutic approach to treat gram-negative sepsis.

Septic shock is the most common cause of death in intensive care units and no effective treatment is available at present. Lipopolysaccharide (LPS) is the primary mediator of Gram-negative sepsis by inducing the production of macrophage-derived cytokines. Previously, we showed that apolipoprotein E (apoE), an established modulator of lipid metabolism, can bind LPS, thereby redirecting LPS from macrophages to hepatocytes in vivo. We now report that intravenously administered LPS strongly increases the serum levels of apoE. In addition, apoE can prevent the LPS-induced production of cytokines and subsequent death in rodents. Finally, apoE-deficient mice show a significantly higher sensitivity toward LPS than control wild-type mice. These findings indicate that apoE may have a physiological role in the protection against sepsis, and recombinant apoE may be used therapeutically to protect against LPS-induced endotoxemia.

Animals↗
PubMed2001

Design and synthesis of a multivalent homing device for targeting to murine CD22.

CD22 is a cell-surface glycoprotein uniquely located on mature B-cells and B-cell derived tumour cells. Current evidence suggests that binding of endogenous ligands to CD22 leads to modulation of B-cell activation by antigen. Incidentally, however, B-cell activation may derail. and lead to an undesired immune response, for example in cases of allergy, rheumatoid arthritis and Crohn's disease. In this situation, synthetic high-affinity ligands for CD22 may be of therapeutic value as inhibitors of B-cell activation. Recent studies have revealed that natural ligands for CD22 contain the trisaccharide NeuAc alpha-2,6-Lac as the basic binding motif. In addition, it has been demonstrated that binding to CD22 is strongly enhanced by multivalent presentation of the basic binding motif (cluster effect). In this paper. the stepwise development of a novel multivalent high-affinity ligand for CD22 is described. In the first stage, a series of monovalent NeuAc alpha-2,6-Glc(Y)X type binding motifs was prepared, and their affinity for murine CD22 was monitored, to obtain more insight into the effect of separate structure elements on ligand recognition. In the second stage, we prepared a trivalent cluster, based on the monovalent motif that displayed the highest affinity for CD22, NeuAc alpha-2,6-GlcNBzNO2OMe (7). This cluster, TRIS(NeuAc alpha-2,6-GlcNBzNO2)3 (52), displayed a more than 58-fold higher affinity for CD22 than the reference structure NeuAc alpha-2,6-LacOMe (10). To our knowledge, the cluster 52 is one of the most potent antagonists for CD22 yet synthesised.

Animals↗
PubMed2001

Scavenger receptor-like receptors for the binding of lipopolysaccharide and lipoteichoic acid to liver endothelial and Kupffer cells.

This study was undertaken to identify the role of scavenger receptors in the catabolism of lipopolysaccharide (LPS) and lipoteichoic acid (LTA). LPS is mainly cleared from the blood by the liver. The Kupffer cells are primarily responsible for this clearance. Although several binding sites have been described for LPS and LTA, only CD14 is involved in LPS signalling. Scavenger receptor type A (SR-A) is expressed in the liver on endothelial cells and Kupffer cells, and macrosialin (class D scavenger receptor) is expressed on Kupffer cells. Fucoidin and poly-I are both good inhibitors of scavenger receptors. Fucoidin significantly reduced the serum clearance of [125I]-LPS and decreased liver uptake of [125I]-LPS by approximately 40%. Poly-I inhibited the binding of [125I]-LPS to isolated Kupffer and endothelial cells by 75%, while poly-A, a polyanionic substrate that does not block scavenger receptors, had no effect. LPS significantly inhibited the binding of acetylated LDL and oxidized LDL (two well-described scavenger receptor ligands) to isolated Kupffer and liver endothelial cells. OxLDL and acLDL did not affect the binding of LPS to these cells. We conclude that on both endothelial cells and Kupffer cells, LPS mainly binds to scavenger receptors, but SR-A and macrosialin contribute to a limited extent to the binding of LPS. Injection of LTA into C57Bl6 mice resulted in a maximal liver uptake of 20% of the injected dose. In the liver, 50% was bound by the Kupffer cells, 20% by parenchymal cells and 30% by liver endothelial cells. The contribution of SR-A to the plasma clearance of LTA was limited. A main component in the catabolism of LTA is the interaction of LTA with plasma lipoproteins, which limit the uptake of LTA by tissues and extend the plasma half-life of LTA.

Animals↗
PubMed2000

FcalphaRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity.

Despite the well-recognized involvement of immunoglobulin (Ig) A in mucosal immunity, the function of its receptor, FcalphaRI (CD89), is poorly understood. The ability of FcalphaRI to activate leukocytes seems to conflict with the proposed anti-inflammatory activity of secretory IgA. We show here that in a transgenic mouse model, inflammatory mediators induced expression of FcalphaRI on Kupffer cells, which enabled efficient phagocytosis in vivo of bacteria coated with serum IgA. Secretory IgA did not initiate phagocytosis. Therefore, interactions between serum IgA and FcalphaRI on Kupffer cells may provide a 'second line of defense' in mucosal immunity, by eliminating invasive bacteria entering through the portal circulation and thus preventing disease.

Animals↗
PubMed1999

Targeted delivery of oligodeoxynucleotides to parenchymal liver cells in vivo.

Anti-sense oligodeoxynucleotides (ODNs) hold great promise for correcting the biosynthesis of clinically relevant proteins. The potential of ODNs for modulating liver-specific genes might be increased by preventing untimely elimination and by improving the local bioavailability of ODNs in the target tissue. In the present study we have assessed whether the local ODN concentration can be enhanced by the targeted delivery of ODNs through conjugation to a ligand for the parenchymal liver cell-specific asialoglycoprotein receptor. A capped ODN (miscellaneous 20-mer sequence) was derivatized with a ligand with high affinity for this receptor, N2-[N2-(N2,N6-bis{N-[p-(beta-d-galactopyranosyloxy) anilino] thiocarbamyl}-L-lysyl)-N6-(N-{p-[beta-D -galactopyranosyloxy] anilino} thiocarbamyl)-L-lysyl]-N6-[N- (p-{beta-D-galactopyranosyloxy}anilino)thiocarbamyl]-L-lysine (L3G4) (Kd 6.5+/-0.2 nM, mean+/-S.D.). Both the uptake studies in vitro and the confocal laser scan microscopy studies demonstrated that L3G4-ODN was far more efficiently bound to and taken up by parenchymal liver cells than underivatized ODN. Studies in vivo in rats showed that hepatic uptake could be greatly enhanced from 19+/-1% to 77+/-6% of the injected dose after glycoconjugation. Importantly, specific ODN accumulation of ODN into parenchymal liver cells was improved almost 60-fold after derivatization with L3G4, and could be attributed to the asialoglycoprotein receptor. In conclusion, the scavenger receptor-mediated elimination pathway for miscellaneous ODN sequences can be circumvented by direct conjugation to a synthetic tag for the asialoglycoprotein receptor. In this manner a crucial requisite is met towards the application of ODNs in vivo to modulate the biosynthesis of parenchymal liver cell-specific genes such as those for apolipoprotein (a), cholesterol ester transfer protein and viral proteins.

Acetylglucosamine↗
PubMed1999

Specific interaction of oxidized low-density lipoprotein with macrophage-derived foam cells isolated from rabbit atherosclerotic lesions.

Interaction of oxidized LDL (OxLDL) with macrophage-derived foam cells is one of the key events in the development and progression of atherosclerosis. To study this interaction, macrophage-derived foam cells were isolated from rabbit atherosclerotic lesions and the expression of scavenger receptors for OxLDL was examined. Atherosclerosis was induced in rabbits by denudation of the large arteries, followed by a hypercholesteremic diet. Macrophage-derived foam cells, characterized by immunostaining with an RAM-11 antibody (a macrophage marker), contained a high content of intracellular lipid. Maximal binding of radiolabeled OxLDL to isolated macrophage-derived foam cells (1652+/-235 ng 125I-OxLDL/mg of cell protein) was 20-fold higher compared with Bmax values of monocytes. Levels of association of OxLDL to macrophage-derived foam cells isolated from atherosclerotic lesions 12 weeks after denudation were >3-fold higher compared with the levels expressed by macrophage-derived foam cells isolated after 6 weeks. Association of 125I-OxLDL could be completely blocked by OxLDL, and partially by acetylated LDL and polyinosinic acid, indicating the presence of a specific binding site for OxLDL on macrophage-derived foam cells. The induction of scavenger receptors for OxLDL on macrophage-derived foam cells during the development of atherosclerosis, as described in this study, may facilitate the lipid accumulation in macrophage-derived foam cells, as observed in advanced atherosclerotic lesions.

Animals↗