Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis

Pablo Canales-Herrerias, Mathieu Uzzan, Akihiro Seki, Rafael S. Czepielewski, Bram Verstockt, Alexandra E. Livanos, Fiona Raso, Alexandra Dunn, Daniel Dai, Andrew Wang, Zainab Al-Taie, Jerome Martin, Thomas Laurent, Huaibin M. Ko, Minami Tokuyama, Michael Tankelevich, Hadar Meringer, Francesca Cossarini, Divya Jha, Azra KrekJohn D. Paulsen, Matthew D. Taylor, Mohammad Zuber Nakadar, Joshua Wong, Emma C. Erlich, Rachel L. Mintz, Emily J. Onufer, Beth A. Helmink, Keshav Sharma, Adam Rosenstein, Danielle Ganjian, Grace Chung, Travis Dawson, Julius Juarez, Vijay Yajnik, Andrea Cerutti, Jeremiah J. Faith, Mayte Suarez-Farinas, Carmen Argmann, Francesca Petralia, Gwendalyn J. Randolph, Alexandros D. Polydorides, Andrea Reboldi, Jean Frederic Colombel, Saurabh Mehandru

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Vedolizumab (VDZ) is a first-line treatment in ulcerative colitis (UC) that targets the α4β7- mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) axis. To determine the mechanisms of action of VDZ, we examined five distinct cohorts of patients with UC. A decrease in naïve B and T cells in the intestines and gut-homing (β7+) plasmablasts in circulation of VDZ-treated patients suggested that VDZ targets gut-associated lymphoid tissue (GALT). Anti-α4β7 blockade in wild-type and photoconvertible (KikGR) mice confirmed a loss of GALT size and cellularity because of impaired cellular entry. In VDZ-treated patients with UC, treatment responders demonstrated reduced intestinal lymphoid aggregate size and follicle organization and a reduction of β7+IgG+ plasmablasts in circulation, as well as IgG+ plasma cells and FcγR-dependent signaling in the intestine. GALT targeting represents a previously unappreciated mechanism of action of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC.

Original languageEnglish
Article numbereadg7549
JournalScience immunology
Volume9
Issue number94
DOIs
StatePublished - Apr 2024

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