A novel multi-parameter assay to dissect the pharmacological effects of different modes of integrin αLβ2 inhibition in whole blood
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 3394650
Author(s) Welzenbach, Karl; Mancuso, Riccardo V.; Krähenbühl, Stephan; Weitz-Schmidt, Gabriele
Author(s) at UniBasel Krähenbühl, Stephan
Year 2015
Title A novel multi-parameter assay to dissect the pharmacological effects of different modes of integrin αLβ2 inhibition in whole blood
Journal British journal of pharmacology
Volume 172
Number 20
Pages / Article-Number 4875-4887
Abstract

The integrin αLβ2 plays central roles in leukocyte adhesion and T cell activation, rendering αLβ2 an attractive therapeutic target. Compounds with different modes of αLβ2 inhibition are in development, currently. Consequently, there is a foreseeable need for bedside assays, which allow assessment of the different effects of diverse types of αLβ2 inhibitors in the peripheral blood of treated patients.; Here, we describe a flow cytometry-based technology that simultaneously quantitates αLβ2 conformational change upon inhibitor binding, αLβ2 expression and T cell activation at the single-cell level in human blood. Two classes of allosteric low MW inhibitors, designated α I and α/β I allosteric αLβ2 inhibitors, were investigated. The first application revealed intriguing inhibitor class-specific profiles.; Half-maximal inhibition of T cell activation was associated with 80% epitope loss induced by α I allosteric inhibitors and with 40% epitope gain induced by α/β I allosteric inhibitors. This differential establishes that inhibitor-induced αLβ2 epitope changes do not directly predict the effect on T cell activation. Moreover, we show here for the first time that α/β I allosteric inhibitors, in contrast to α I allosteric inhibitors, provoked partial downmodulation of αLβ2, revealing a novel property of this inhibitor class.; The multi-parameter whole blood αLβ2 assay described here may enable therapeutic monitoring of αLβ2 inhibitors in patients' blood. The assay dissects differential effect profiles of different classes of αLβ2 inhibitors.

Publisher Nature Publishing Group
ISSN/ISBN 0007-1188
edoc-URL http://edoc.unibas.ch/41407/
Full Text on edoc No
Digital Object Identifier DOI 10.1111/bph.13256
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/26224111
ISI-Number WOS:000363656000008
Document type (ISI) Article
 
   

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