The α4β1 homing pathway is essential for ileal homing of Crohn's disease effector T cells in vivo

Zundler, Sebastian, Fischer, Anika, Schillinger, Daniella, Binder, Marie-Theres, Atreya, Raja, Rath, Timo, Lopez-Posadas, Rocio, Voskens, Caroline, Watson, Alastair, Atreya, Imke, Neufert, Clemens and Neurath, Markus (2017) The α4β1 homing pathway is essential for ileal homing of Crohn's disease effector T cells in vivo. Inflammatory Bowel Diseases, 23 (3). pp. 379-391. ISSN 1078-0998

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Abstract

The precise mechanisms controlling homing of T effector (Teff) cells to the inflamed gut in Crohn’s disease (CD) are still unclear and clinical outcome data from inflammatory bowel disease (IBD) patients treated with the anti-α4β7 integrin antibody vedolizumab suggest differences between ulcerative colitis (UC) and CD. Methods: Expression of homing molecules was studied with flow cytometry and immunohistochemistry. Their functional role was investigated in in vitro adhesion assays and in a humanized mouse model of T cell homing to the inflamed gut in vivo. Results: Despite in vitro blockade of CD Teff adhesion to MAdCAM-1 and in contrast to previous oberservations in UC, anti-α4β7 treatment did not result in reduced Teff cell homing to the gut in vivo. However, the integrin α4β1 was expressed in higher levels on Teffs from CD patients compared with controls, while its expression in the peripheral blood declined and its expression in the intestine increased during the course of clinical vedolizumab treatment. Consistently, adhesion of CD Teffs to VCAM-1 was blocked by inhibition of α4 and α4β1 in vitro. Moreover, in vivo homing of CD Teffs to the inflamed ileum was reduced by inhibition of α4 and α4β1 integrins, but not α4β7 integrins. Conclusions: Our findings suggest that Teff cell homing to the ileum via the axis α4β1 – VCAM-1 is an essential and non-redundant pathway in CD in vivo possibly affecting efficacy of clinical treatment with anti-adhesion compounds.

Item Type: Article
Faculty \ School: Faculty of Medicine and Health Sciences > Norwich Medical School
Depositing User: Pure Connector
Date Deposited: 17 Jan 2017 00:07
Last Modified: 22 Apr 2020 01:59
URI: https://ueaeprints.uea.ac.uk/id/eprint/62112
DOI: 10.1097/MIB.0000000000001029

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