Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewis x antagonist TBC1269: Preferential activity against neutrophil adhesion in vitro

Davenpeck, Kelly L.; Berens, Kurt L.; Dixon, Richard A. F.; Dupre, Brian; Bochner, Bruce S.

doi:10.1067/mai.2000.105121

Cited by 55 publications

(35 citation statements)

References 26 publications

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“…The damage caused by hemorrhagic shock was diminished after pretreatment with BIMO (21). Furthermore, BIMO blockade of selectin/PSGL-1 interaction inhibited the PSGL-1-induced expression of adhesion molecules (19). The involvement of selectins in the pathogenesis of renal I/R injury was confirmed by results obtained with another selectin inhibitor, glycyrrhizin (22).…”

supporting

confidence: 67%

“…In vitro studies examined the competitive inhibitory effects of BIMO on the binding of beads coated with human E-, P-, or L-selectin/IgG fusion protein to HL60 cells expressing natural sLe x (19). Although the inactive control was ineffective, a 50% inhibitory effect (IC 50 ) was achieved by BIMO at 500 M for E-selectin, 70 M for P-selectin, and 560 M for L-selectin.…”

mentioning

confidence: 99%

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Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

Langer

Wang

Stepkowski

et al. 2004

Journal of the American Society of Nephrology

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Abstract. Binding of the P-, L-, and E-selectins to sialyl Lewis (CI Ͻ1 is synergistic; CI ϭ 1 is additive; and CI Ͼ1 is antagonistic). Similarly, BIMO interacted synergistically with sirolimus (CI ϭ 0.64) and FTY720 (CI ϭ 0.22). While the mechanism of immunosuppression was being analyzed, decreased infiltration of CD4 ϩ , CD8 ϩ , and macrophages on day 7 after grafting was observed. Multiple cytokines were also expressed, including IL-1␣, IL-1␤, IL-2, IL-4, IL-6, IL-10, IL-12, IL-18, TNF-␣, and IFN-␥ in kidney allografts on days 3, 5, and 7 after grafting, as measured by a ribonuclease protection assay. Furthermore, at similar time points, BIMO treatment reduced intragraft expression of P-selectin glycoprotein ligand-1, CX 3 CL1, CCL19, CCL20, and CCL2. Thus, BIMO blocks allograft rejection by reduction of intragraft expression of cytokines and chemokines.Whereas nearly all cells in an adult human are sessile, the majority of leukocytes provide a mobile defense of the individual's integrity (1). Precursors of leukocytes continuously undergo differentiation in the bone marrow and the thymus, whereas mature leukocytes continuously traffic between the spleen and the lymph nodes. Efficient deployment to an inflammatory site requires polarization, mobilization, and migration of leukocytes during processes that are controlled by adhesion molecules and chemokines (2). These molecules participate in the process of ischemia/reperfusion (I/R), as well as in acute and chronic rejection responses toward organ allografts (3,4).Adhesive interactions with the vascular endothelium initiate the migration of leukocytes to sites of inflammation. In this cascade of events (rolling, attachment, spreading, and transendothelial migration), the selectin family (P-, E-, and L-selectins) is largely involved in rolling and attachment (5). Rolling is initiated by the interaction of selectins with sialyl Lewis x (sLe x ) ligand (6); all selectins have an NH 2 -terminal, lectinlike domain binding to sLe x and other related ligands in a Ca 2ϩ -dependent manner (7). Two selectins are expressed on endothelial cells, namely, P-selectins, which are stored in granules and rapidly translocated to the cell surface, and E-selectins, which are induced by inflammatory cytokines (8). Within minutes after reperfusion, endothelial cells express P-selectins that mediate leukocyte rolling over the vascular lining.The main ligand for P-selectin is P-selectin glycoprotein ligand-1 (PSGL-1), which is a disulfide-bonded homodimeric mucin-like glycoprotein expressed on leukocytes, platelets, and CD34 ϩ cells (9). Functional PSGL-1 is modified with sialylation and fucosylation of O-linked sugars, as well as sulfation of tyrosine residues on the N-terminus (10). Engagement of PSGL-1 by P-selectins slows the movement of leukocytes and sparks a cascade of signaling pathways, leading to the expression of multiple adhesion molecules (11). During rolling, the leukocytes start expressing integrins triggered by cytokines and

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supporting

confidence: 67%

mentioning

confidence: 99%

Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

Langer

Wang

Stepkowski

et al. 2004

Journal of the American Society of Nephrology

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“…TBC1269 is a nonoligosaccharide sLe x antagonist and has been shown to block binding to all selectins (39,40). In general, eosinophils have been shown in other studies, as well as the current, to require much more TBC1269 to produce an inhibitory effect compared with the neutrophils (40). In this model of intestinal migration of eosinophils, TBC1269 compound displays potent inhibitory effect, resulting in almost complete abolishment of the migration process.…”

Section: Discussionmentioning

confidence: 95%

“…sLe x binds to the three known selectins; therefore, compounds that inhibit sLe x act as a selectin antagonist. TBC1269 is a nonoligosaccharide sLe x antagonist and has been shown to block binding to all selectins (39,40). In general, eosinophils have been shown in other studies, as well as the current, to require much more TBC1269 to produce an inhibitory effect compared with the neutrophils (40).…”

Section: Discussionmentioning

confidence: 99%

Role of Selectins in the Intestinal Epithelial Migration of Eosinophils

2005

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Understanding the mechanisms by which eosinophils migrate into and across the intestinal epithelium can provide alternative therapeutic targets for conditions characterized by eosinophilic cryptitis and crypt abscesses. Eosinophil migration is dependent on adhesion molecules such as selectins. Human eosinophils express L-selectin and P-selectin counterligand P-selectin glycoprotein ligand-1 (PSGL-1). The tetrasaccharide sialyl Lewis x (sLe x ) binds to all three selectins, so compounds that mimic sLe x , such as TBC1269, are potential antagonists. We hypothesized that eosinophils migrate from the basolateral to the apical surface of intestinal epithelium through the orchestrated effects of selectins. TBC1269 was added to fluorescently labeled HL-60 clone 15 eosinophils as well as human blood eosinophils, in incremental amounts. Subsequently, blocking antibodies toward L-selectin and PSGL-1 were used in a similar manner. HL-60 eosinophils were allowed to migrate into T-84 monolayers. The number of migrated HL-60 cells was calculated by comparing fluorescence with known cell densities. HL-60 and human eosinophils that were undergoing migration were significantly lower in the presence of TBC1269. This effect was concentration dependent, and near complete inhibition of migration was seen at a TBC1269 concentration of 10 mg/mL. In addition, HL-60 eosinophil migration was significantly lower in the presence of the blocking antibodies to PSGL-1 and L-selectin (39.2 and 51.6% inhibition, respectively). Simultaneous blocking of PSGL-1 and L-selectin resulted in inhibition of 76.0% of the migration. The results of this study suggest a major role for selectins in the intestinal epithelial migration of differentiated eosinophils. sLe x , Lselectin, and the P-selectin counterligand PSGL-1 can be potential therapeutic targets. The gastrointestinal tract represents the largest reservoir of eosinophils within the body. In the gut, eosinophils play an important role in several inflammatory disorders (1). During these conditions, the eosinophils migrate into the intestinal lumen, forming eosinophilic crypt abscesses (2). Eosinophil products then are released, which can contribute to epithelial damage (3).The infiltration of the leukocytes to the areas of injury and inflammation is accomplished by the coordinated actions of cellular adhesion molecules under the direction of chemokine signaling. Three families of adhesion molecules contribute to eosinophil migration: selectins, integrins, and immunoglobulins. The family of selectins consists of three members: L-, P-, and E-selectins. The interaction between the selectins and their ligands is carbohydrate based. Therefore, compounds such as the tetrasaccharide sialyl Lewis x (sLe x ) are known to bind to all selectins, acting as an antagonist (4).The process of eosinophil migration across the endothelium has been widely investigated, yet little is known about eosinophil-epithelial interactions in the gut. Measures that can prevent eosinophil recruitment into the intestinal epitheliu...

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“…In an ovine model of asthma, TBC1269 reduced disease severity. 1 TBC1269 reduces neutrophil infiltration in vitro, 12 and we have shown previously that TBC1269 significantly reduced neutrophil infiltration and vascular leakage of protein, and tended to decrease membrane damage, in calves inoculated with M. haemolytica. 9,28 Characteristic of M. haemolytica pneumonia are the dense infiltrates of neutrophils in the airways and alveoli.…”

mentioning

confidence: 99%

A Selectin Inhibitor Decreases Neutrophil Infiltration during AcuteMannheimia haemolyticaPneumonia

Radi

Brogden

Dixon³

et al. 2002

Vet Pathol

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Abstract. The degree to which the selectin inhibitor TBC1269 reduces neutrophil infiltration in specific microscopic locations of the lung during acute pneumonia of neonates was determined. Neonatal calves were inoculated intrabronchially with Mannheimia (Pasteurella) haemolytica or saline, and lung tissue was collected at 2 and 6 hours postinoculation (PI). One 6-hour group inoculated with M. haemolytica received TBC1269 intravenously before and after inoculation with M. haemolytica. Infiltrates of neutrophils were significantly higher in the alveolar lumen and septae but lower in the bronchial lumen and epithelium at 6 hours PI than at 2 hours PI. Significantly fewer neutrophils (P Ͻ 0.05) were present in the alveolar lumen and septae, and the bronchiolar lumen and lamina propria in the lungs of TBC1269-treated calves compared with untreated calves at 6 hours PI. TBC1269 did not alter the infiltration into bronchi and blood vessels or the expression of the selectin-independent adhesion molecule, ICAM-1. This work suggests that during acute pneumonia of neonates 1) neutrophil infiltrates progressively increase in the alveolar lumens and septae but decrease in the bronchial lumen and epithelium with time, 2) TBC1269 reduces neutrophil infiltration into specific regions of alveoli and bronchioles rather than uniformly throughout the lung, and 3) selectin inhibition does not affect the location and intensity of ICAM-1 expression.

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Inhibition of adhesion of human neutrophils and eosinophils to P-selectin by the sialyl Lewis x antagonist TBC1269: Preferential activity against neutrophil adhesion in vitro

Cited by 55 publications

References 26 publications

Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

Selectin Inhibitor Bimosiamose Prolongs Survival of Kidney Allografts by Reduction in Intragraft Production of Cytokines and Chemokines

Role of Selectins in the Intestinal Epithelial Migration of Eosinophils

A Selectin Inhibitor Decreases Neutrophil Infiltration during AcuteMannheimia haemolyticaPneumonia

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