Abstract
Leukocyte adhesion molecules are involved in cell recruitment in an allergic airway response and therefore provide a target for pharmaceutical intervention. Neutrophil inhibitory factor (NIF), derived from canine hookworm (Ancylostoma caninum), binds selectively and competes with the A-domain of CD11b for binding to ICAM-1. The effect of recombinant NIF was investigated. Intranasal administration of rNIF reduced pulmonary eosinophilic infiltration, goblet cell hyperplasia, and Th2 cytokine production in OVA-sensitized mice. In vitro, transendothelial migration of human blood eosinophils across IL-4-activated umbilical vein endothelial cell (HUVEC) monolayers was inhibited by rNIF (IC50: 4.6 ± 2.6 nM; mean ± SEM), but not across TNF or IL-1-activated HUVEC monolayers. Treatment of eosinophils with rNIF together with mAb 60.1 directed against CD11b or mAb 107 directed against the metal ion-dependent adhesion site (MIDAS) of the CD11b A-domain resulted in no further inhibition of transendothelial migration suggesting shared functional epitopes. In contrast, rNIF increased the inhibitory effect of blocking mAbs against CD18, CD11a, and VLA-4. Together, we show that rNIF, a selective antagonist of the A-domain of CD11b, has a prominent inhibitory effect on eosinophil transendothelial migration in vitro, which is congruent to the in vivo inhibition of OVA-induced allergic lung inflammation.
Highlights
Allergic asthma has increased dramatically in prevalence and severity over the last two decades
Transendothelial migration of human blood eosinophils across IL-4-activated umbilical vein endothelial cell (HUVEC) monolayers was inhibited by Recombinant Neutrophil Inhibitory Factor transendothelial migration (TEM) (rNIF) (IC50: 4.6 ± 2.6 nM; mean ± SEM), but not across TNF or IL-1-activated HUVEC monolayers
Treatment of eosinophils with rNIF together with mAb 60.1 directed against CD11b or mAb 107 directed against the metal ion-dependent adhesion site (MIDAS) of the CD11b A-domain resulted in no further inhibition of transendothelial migration suggesting shared functional epitopes
Summary
Allergic asthma has increased dramatically in prevalence and severity over the last two decades. The A-domain, is ≈200 amino acid peptide within the CD11b molecule binding divalent cations and representing a major recognition site for iC3b, fibrinogen, and factor X of the coagulation cascade [17]. By virtue of these multiple but distinct binding sites, the A-domain plays an essential role in phagocytosis, cytotoxicity, and leukocyte trafficking to inflammatory sites. This study shows that rNIF blocks transmigration of eosinophils but not neutrophils across endothelial cell monolayers in culture and inhibits eosinophil recruitment and infiltration, goblet cell hyperplasia, mucus secretion, and Th2 cytokine production in the OVA-induced lung inflammation model in mice
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