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Downstream effect profiles discern different mechanisms of integrin αLβ2 inhibition

Mancuso, Riccardo V. and Welzenbach, Karl and Steinberger, Peter and Krähenbühl, Stephan and Weitz-Schmidt, Gabriele. (2016) Downstream effect profiles discern different mechanisms of integrin αLβ2 inhibition. Biochemical Pharmacology, 119. pp. 42-55.

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Abstract

The integrin leucocyte function-associated antigen-1 (αLβ2, LFA-1) plays crucial roles in T cell adhesion, migration and immunological synapse (IS) formation. Consequently, αLβ2 is an important therapeutic target in autoimmunity. Three major classes of αLβ2 inhibitors with distinct modes of action have been described to date: Monoclonal antibodies (mAbs), small molecule α/β I allosteric and small molecule α I allosteric inhibitors. The objective of this study was to systematically compare these three modes of αLβ2 inhibition for their αLβ2 inhibitory as well as their potential agonist-like effects. All inhibitors assessed were found to potently block αLβ2-mediated leucocyte adhesion. None of the inhibitors induced ZAP70 phosphorylation, indicating absence of agonistic outside-in signalling. Paradoxically, however, the α/β I allosteric inhibitor XVA143 induced conformational changes within αLβ2 characteristic for an intermediate affinity state. This effect was not observed with the α I allosteric inhibitor LFA878 or the anti-αLβ2 mAb efalizumab. On the other hand, efalizumab triggered the unscheduled internalization of αLβ2 in CD4+ and CD8+ T cells while LFA878 and XVA143 did not affect or only mildly reduced αLβ2 surface expression, respectively. Moreover, efalizumab, in contrast to the small molecule inhibitors, disturbed the fine-tuned internalization/recycling of engaged TCR/CD3, concomitantly decreasing ZAP70 expression levels. In conclusion, different modes of αLβ2 inhibition are associated with fundamentally different biologic effect profiles. The differential established here is expected to provide important translational guidance as novel αLβ2 inhibitors will be advanced from bench to bedside.
Faculties and Departments:03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Clinical Pharmacology (Krähenbühl)
05 Faculty of Science
05 Faculty of Science > Departement Pharmazeutische Wissenschaften
UniBasel Contributors:Mancuso, Riccardo and Krähenbühl, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Elsevier
ISSN:0006-2952
e-ISSN:1873-2968
Note:Publication type according to Uni Basel Research Database: Journal article
Language:English
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Last Modified:15 Sep 2020 12:59
Deposited On:15 Sep 2020 12:59

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