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Downstream effect profiles discern different mechanisms of integrin alphaLbeta2 inhibition

Mancuso, R. V. and Welzenbach, K. and Steinberger, P. and Krahenbuhl, S. and Weitz-Schmidt, G.. (2016) Downstream effect profiles discern different mechanisms of integrin alphaLbeta2 inhibition. Biochem Pharmacol, 119. pp. 42-55.

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Official URL: https://edoc.unibas.ch/62285/

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Abstract

The integrin leucocyte function-associated antigen-1 (alphaLbeta2, LFA-1) plays crucial roles in T cell adhesion, migration and immunological synapse (IS) formation. Consequently, alphaLbeta2 is an important therapeutic target in autoimmunity. Three major classes of alphaLbeta2 inhibitors with distinct modes of action have been described to date: Monoclonal antibodies (mAbs), small molecule alpha/beta I allosteric and small molecule alpha I allosteric inhibitors. The objective of this study was to systematically compare these three modes of alphaLbeta2 inhibition for their alphaLbeta2 inhibitory as well as their potential agonist-like effects. All inhibitors assessed were found to potently block alphaLbeta2-mediated leucocyte adhesion. None of the inhibitors induced ZAP70 phosphorylation, indicating absence of agonistic outside-in signalling. Paradoxically, however, the alpha/beta I allosteric inhibitor XVA143 induced conformational changes within alphaLbeta2 characteristic for an intermediate affinity state. This effect was not observed with the alpha I allosteric inhibitor LFA878 or the anti-alphaLbeta2 mAb efalizumab. On the other hand, efalizumab triggered the unscheduled internalization of alphaLbeta2 in CD4+ and CD8+ T cells while LFA878 and XVA143 did not affect or only mildly reduced alphaLbeta2 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 alphaLbeta2 inhibition are associated with fundamentally different biologic effect profiles. The differential established here is expected to provide important translational guidance as novel alphaLbeta2 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)
UniBasel Contributors:Krähenbühl, Stephan
Item Type:Article, refereed
Article Subtype:Research Article
ISSN:1873-2968 (Electronic) 0006-2952 (Linking)
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:25 May 2020 08:13
Deposited On:25 May 2020 08:13

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