Therapeutic inhibition of carbohydrate-protein interactions in vivo.

Lowe, John B.; Ward, Peter A.

doi:10.1172/jci119244

Cited by 81 publications

(47 citation statements)

References 39 publications

(41 reference statements)

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“…Potential new therapeutic strategies include the use of antagonists of endothelial cell activation 79 and inhibitors of P-selectin-ligand interactions, 80 the latter of which includes heparin. 47,74,81,82 The published suggestion that heparin therapy may be efficacious in reducing the frequency of sickle cell pain crises 83 could be verified presently, because there is much clinical experience using heparin for other vaso-occlusive diseases.…”

Section: Discussionmentioning

confidence: 99%

P-selectin mediates the adhesion of sickle erythrocytes to the endothelium

Matsui

Borsig

Rosen

et al. 2001

Blood

214

191

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The adherence of sickle red blood cells (RBCs) to the vascular endothelium may contribute to painful vaso-occlusion in sickle cell disease. Sickle cell adherence involves several receptor-mediated processes and may be potentiated by the up-regulated expression of adhesion molecules on activated endothelial cells. Recent results showed that thrombin rapidly increases the adhesivity of endothelial cells for sickle erythrocytes. The current report presents the first evidence for the novel adhesion of normal and, to a greater extent, sickle RBCs to endothelial Pselectin. Studies of the possible interaction of erythrocytes with P-selectin revealed that either P-selectin blocking monoclonal antibodies or sialyl Lewis tetrasaccharide inhibits the enhanced adherence of normal and sickle cells to thrombin-treated endothelial cells. Both RBC types also adhere to immobilized recombinant P-selectin. Pretreating erythrocytes with sialidase reduces their adherence to activated endothelial cells and to immobilized recombinant P-selectin. Herein the first evidence is presented for the binding of normal or sickle erythrocytes to P-selectin. This novel finding suggests that P-selectin inhibition be considered as a potential approach to therapy for the treatment of painful vasoocclusion in sickle cell disease. IntroductionThe interaction of P-selectin and its ligands contributes to the specificity of interactions among endothelial cells, platelets, and leukocytes during inflammation, coagulation, and atherosclerosis. [1][2][3][4][5][6][7][8] The expression of P-selectin on endothelial cells and platelets requires activation of these cells by specific biologic response modifiers, such as thrombin, which has the capacity in both cell types to trigger rapid translocation of P-selectin from intracellular storage granules to the membrane surface and in endothelial cells to induce also slower transcriptional up-regulation of the P-selectin gene. [9][10][11] Another requisite for P-selectin-mediated adhesive interactions is a P-selectin ligand whose specificity is conferred by the particular transferases that generate its unique carbohydrate composition. 1,4,[6][7][8]12,13 Erythrocytes are not considered to participate in these receptor-mediated processes, 8 because normal red blood cells (RBCs) are not known to bear selectin ligands or to bind to P-selectin. 14 The conventional view that erythrocyte sickling in small blood vessels causes the painful vaso-occlusion of sickle cell disease does not explain why only 5% of patients account for 30% of pain crises in this common debilitating genetic condition. 15,16 An emerging hypothesis is that vaso-occlusion involves factors besides erythrocyte sickling. The adherence of sickle cells to vascular endothelium may be particularly important to vaso-occlusion. 17 Hebbel and colleagues found that sickle erythrocytes are abnormally adherent to endothelial cells in vitro 18 and that the adhesivity of sickle RBCs in vitro correlates with vaso-occlusive severity. 19 Kaul and associates determined t...

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Section: Discussionmentioning

confidence: 99%

P-selectin mediates the adhesion of sickle erythrocytes to the endothelium

Matsui

Borsig

Rosen

et al. 2001

Blood

214

191

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“…The vascular endothelium is a dynamic and complex system that possesses many secretory, synthetic, immunologic, and metabolic functions (18). The contribution of carbohydrates to endothelial function is best exemplified by the selectin family of adhesion molecules, which recognize sialyl Lewis x -and sialyl Lewis a -containing structures (12)(13)(14). Also, unusual anionic oligosaccharides such as sialyl Lewis x/a as well as sulfosialyl Lewis x/a , Man-6-phosphate (19), polysialic acid (20), and GalNAc-4-sulfate (21) have been noted to be more involved in mediating specific biological actions than the more common neutral glycans.…”

Section: Discussionmentioning

confidence: 99%

“…Selectins mediate the initial rolling and tethering of circulating neutrophils. L-selectin is constitutively expressed by most leukocytes, and Pand E-selectins are expressed by activated endothelial cells following exposure to inflammatory conditions (12)(13)(14). Concomitant up-regulation of ␤ 2 integrins on the neutrophils are largely responsible for stronger adhesive interactions with intercellular adhesion molecules (ICAM-1 and ICAM2).…”

Section: Monoclonal Ab Gb31 Inhibits Leukocyte Influx In a Mouse Modmentioning

confidence: 99%

A Novel Anionic Modification of N-Glycans on Mammalian Endothelial Cells Is Recognized by Activated Neutrophils and Modulates Acute Inflammatory Responses

Srikrishna

Toomre²,

Manzi³

et al. 2001

The Journal of Immunology

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We previously reported an unusual carboxylated modification on N-glycans isolated from whole bovine lung. We have now raised IgG mAbs against the modification by immunization with biotinylated aminopyridine-derivatized glycans enriched for the anionic species and screening for Abs whose reactivities were abrogated by carboxylate neutralization of bovine lung glycopeptides. One such Ab (mAb GB3.1) was inhibited by carboxylated bovine lung glycopeptides and other multicarboxylated molecules, but not by glycopeptides in which the carboxylate groups were modified. The Ab recognized an epitope constitutively expressed on bovine, human, and other mammalian endothelial cells. Stimulated, but not resting, neutrophils bound to immobilized bovine lung glycopeptides in a carboxylate-dependent manner. The binding of activated neutrophils to immobilized bovine lung glycopeptides was inhibited both by mAb GB3.1 and by soluble glycopeptides in a carboxylate-dependent manner. The Ab also inhibited extravasation of neutrophils and monocytes in a murine model of peritoneal inflammation. This inhibition of cell trafficking correlated with the increased sequestration but reduced transmigration of leukocytes that were found to be adherent to the endothelium of the mesenteric microvasculature. Taken together, these results indicate that these novel carboxylated N-glycans are constitutively expressed on vascular endothelium and participate in acute inflammatory responses by interaction with activated neutrophils.

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“…Protein±carbohydrate interactions are ubiquitous in biology and are important in in¯am-mation, immune response and infection (Dwek, 1996;Ni & Tizard, 1996;Lowe & Ward, 1997). As such, these interactions are clear targets for therapeutic intervention.…”

Section: Introductionmentioning

confidence: 99%

A general method for co-crystallization of concanavalin A with carbohydrates

Moothoo

Naismith

1999

Acta Crystallogr D Biol Cryst

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A small grid of conditions has been developed for co-crystallization of the plant lectin concanavalin A (conA) and polysaccharides. Crystals have been obtained of complexes of conA with 1-2 mannobiose, 1-methyl 1-2 mannobiose, fructose, a trisaccharide and a pentasaccharide. The crystals diffract to resolutions of 1.75±2.7 A Ê using a copper rotating-anode source. The crystals are grown in the presence of polyethylene glycol 6K [10±20%(w/v)] at around pH 6.0. Optimization for each particular carbohydrate requires small adjustments in the conditions; however, all complexes give some crystalline precipitate in this limited grid. The 1-2 mannobiose complex crystals diffract to 1.75 A Ê with space group I222 and cell dimensions a = 91.7, b = 86.8, c = 66.6 A Ê . One monomer is present in the asymmetric unit. The 1-methyl 1-2 mannobioside complex crystallizes in space group P2 1 2 1 2 1 , cell dimensions a = 119.7, b = 119.7, c = 68.9 A Ê and diffract to 2.75 A Ê . One tetramer is present in the asymmetric unit. Two crystal forms of the conA±fructose complex have been obtained. The ®rst has space group P2 1 2 1 2 1 , cell dimensions a = 121.7, b = 119.9, c = 67.3 A Ê with a tetramer in the asymmetric unit and diffracts to 2.6 A Ê . The second crystallizes in space group C222 1 , cell dimensions a = 103.3, b = 117.9, c = 254.3 A Ê with two dimers in the asymmetric unit and diffracts to 2.42 A Ê . Structures and crystallization of the trisaccharide±conA and pentasaccharide±conA complexes have already been reported. In all complexes, the protein is found as a tetramer, although varying combinations of non-crystallographic and crystallographic symmetry are involved in generating the tetramer. The precise packing of the tetramer varies from crystal to crystal and it is likely that this variability facilitates crystallization.

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Therapeutic inhibition of carbohydrate-protein interactions in vivo.

Cited by 81 publications

References 39 publications

P-selectin mediates the adhesion of sickle erythrocytes to the endothelium

P-selectin mediates the adhesion of sickle erythrocytes to the endothelium

A Novel Anionic Modification of N-Glycans on Mammalian Endothelial Cells Is Recognized by Activated Neutrophils and Modulates Acute Inflammatory Responses

A general method for co-crystallization of concanavalin A with carbohydrates

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