title: Neutrophil Inhibitory Factor Selectively Inhibits the Endothelium-Driven Transmigration of Eosinophils In Vitro and Airway Eosinophilia in OVA-Induced Allergic Lung Inflammation.
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 Th(2) 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 (IC(50): 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.
authors.affiliation: UMR7355, CNRS, Orleans, France ; Experimental and Molecular Immunology and Neurogenetics, University of Orleans, Orleans, France ; Institute for Clinical and Biomedical Research Thurgau, 9548 Matzingen, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Schnyder-Candrian
authors.forename: Isabelle
authors.initials: I
authors.lastname: Maillet
authors.forename: Marc
authors.initials: M
authors.lastname: Le Bert
authors.forename: Lea
authors.initials: L
authors.lastname: Brault
authors.forename: Muazzam
authors.initials: M
authors.lastname: Jacobs
authors.forename: Bernhard
authors.initials: B
authors.lastname: Ryffel
authors.forename: Bruno
authors.initials: B
authors.lastname: Schnyder
authors.forename: René
authors.initials: R
authors.lastname: Moser