Journal
VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY
Volume 130, Issue 1-2, Pages 79-87Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.vetimm.2009.01.011
Keywords
alpha(4)beta(1); CD49d/CD29; VLA-4; Recurrent airway obstruction; Heaves; Horse
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The purpose of this study was to characterize the 001 receptor (CD49d/CD29, very late antigen-4,VLA-4)on circulating equine leukocytes and to evaluate the intrinsic potency of an alpha(4)beta(1) receptor antagonist (Compound B) in the horse. Ultimately, these studies would allow us to determine the suitability of treating recurrent airway obstruction (RAO; heaves) affected horses by blocking the cellular recruitment of lymphocytes and neutrophils into the lung. The data demonstrates the alpha(4)beta(1) integrin is present on horse lymphocytes and neutrophils (fluorescence-assisted cell sorter, FACS) and can bind low molecular weight alpha(4)beta(1) antagonists (Compounds A and B) with high affinity. K-D values for the binding of Compound A to non-activated alpha(4)beta(1) on isolated horse PBMCs (peripheral blood mononuclear cells) and activated neutrophils were 17 pM and 27 pM, respectively. Compound B was identified as a suitable antagonist for performing a series of in vivo experiments. Compound B was found to possess excellent potency in horse whole blood, possessing IC50 and IC90 values of39 pM and 172 pM, respectively. This represents a 3.9-fold molar excess of drug over the alpha(4)beta(1) concentration in blood. Following oral administration of Compound B (5 mg/kg) to beagle dogs and rhesus monkeys, rapid and sustained alpha(4)beta(1) receptor occupancy (>80%) was achieved and maintained for a period of 24 h. When Compound B was administered intravenously to the horse, by either a slow or rapid infusion at a dose of 0.3 mg/kg, receptor blockade of>80% was observed out to 24 h with a concomitant leukocytosis. We believe that Compound B possesses suitable intrinsic and pharmacological properties to be evaluated clinically in horses affected by RAO. (C) 2009 Elsevier B.V. All rights reserved.
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