Characterization of alpha(4)beta(1) (CD49d/CD29) on equine leukocytes: potential utility of a potent alpha(4)beta(1) (CD49d/CD29) receptor antagonist in the treatment of equine heaves (recurrent airway obstruction).
Abstract: The purpose of this study was to characterize the alpha(4)beta(1) 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 IC(50) and IC(90) values of 39 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.
Publication Date: 2009-02-04 PubMed ID: 19250687DOI: 10.1016/j.vetimm.2009.01.011Google Scholar: Lookup
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Summary
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This research explores the alpha(4)beta(1) receptor in horse leukocytes and the effectiveness of a particular antagonist, Compound B, in treating recurrent airway obstruction (also known as equine heaves) in horses.
Alpha(4)Beta(1) Receptor and Compound B
- Alpha(4)beta(1) also known as CD49d/CD29 or VLA-4, is a receptor present on horse leukocytes. This research aimed to characterize this receptor to study its properties and potential applications.
- The examination of the receptor’s antagonist, Compound B, was carried out to evaluate its effectiveness. An antagonist is a substance that interferes with or inhibits the physiological action of another, in this case, the alpha(4)beta(1) receptor.
- The objective is to see if by blocking alpha(4)beta(1), thus preventing the cellular recruitment of lymphocytes and neutrophils into the lung, could effectively treat RAO in horses.
Detailed Findings
- Researchers found that alpha(4)beta(1) receptor was present on horse lymphocytes and neutrophils, and could bind to the antagonists (Compounds A and B) with high potency.
- KD values, which represent the equilibrium between receptor and the agonist or antagonist, for the binding of Compound A to non-activated alpha(4)beta(1) on isolated horse PBMCs and activated neutrophils, were found to be 17 pM and 27 pM, respectively. This indicates high potential for stopping the receptor’s action.
- Compound B was selected for further study due to its high potency. It was determined that it possessed excellent potency in horse whole blood, with IC(50) and IC(90) values at 39 pM and 172 pM, respectively.
- Treatments with Compound B (5 mg/kg) in beagle dogs and rhesus monkeys showed rapid and sustained alpha(4)beta(1) receptor occupancy of over 80% which was maintained for a period of 24 hours. This suggests that Compound B could be an effective antagonist for alpha(4)beta(1).
Conclusion
- When Compound B was administered intravenously to the horse, by either a slow or rapid infusion, a receptor blockade of over 80% was observed within 24 hours with a corresponding leukocytosis (increase in the number of white blood cells).
- As a result of this study, Compound B has been identified as having a strong potential to be evaluated clinically as a treatment for horses affected by RAO, due to its potency and the sustained blockage of the alpha(4)beta(1) receptor it achieves.
Cite This Article
APA
Treonze KM, Alves K, Fischer P, Hagmann WK, Hora D, Kulick A, Vakerich K, Smith ND, Lingham RB, Maniar S, Reger TS, Zunic J, Munoz B, Prasit P, Nicholson D, Si Q, Judd K, Nicolich S, Kellerhouse P, Thompson D, Mumford RA.
(2009).
Characterization of alpha(4)beta(1) (CD49d/CD29) on equine leukocytes: potential utility of a potent alpha(4)beta(1) (CD49d/CD29) receptor antagonist in the treatment of equine heaves (recurrent airway obstruction).
Vet Immunol Immunopathol, 130(1-2), 79-87.
https://doi.org/10.1016/j.vetimm.2009.01.011 Publication
Researcher Affiliations
- Department of Immunology, Merck Research Laboratories, PO Box 2000, Rahway, NJ 07065, USA. kelly_treonze@merck.com
MeSH Terms
- Airway Obstruction / blood
- Airway Obstruction / drug therapy
- Airway Obstruction / immunology
- Airway Obstruction / veterinary
- Animals
- Binding, Competitive
- Dogs
- Female
- Flow Cytometry / veterinary
- Horse Diseases / blood
- Horse Diseases / drug therapy
- Horse Diseases / immunology
- Horses
- Integrin alpha4beta1 / antagonists & inhibitors
- Integrin alpha4beta1 / immunology
- Leukocytes / immunology
- Macaca mulatta
- Male
- Rats
- Rats, Sprague-Dawley
Citations
This article has been cited 2 times.- Merlo B, Baldassarro VA, Flagelli A, Marcoccia R, Giraldi V, Focarete ML, Giacomini D, Iacono E. Peptide Mediated Adhesion to Beta-Lactam Ring of Equine Mesenchymal Stem Cells: A Pilot Study. Animals (Basel) 2022 Mar 15;12(6).
- Pfeiffenberger M, Bartsch J, Hoff P, Ponomarev I, Barnewitz D, Thöne-Reineke C, Buttgereit F, Gaber T, Lang A. Hypoxia and mesenchymal stromal cells as key drivers of initial fracture healing in an equine in vitro fracture hematoma model. PLoS One 2019;14(4):e0214276.
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