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

Authors :
Pablo Canales-Herrerias
Mathieu Uzzan
Akihiro Seki
Rafael S. Czepielewski
Bram Verstockt
Alexandra Livanos
Fiona Raso
Alexandra Dunn
Daniel Dai
Andrew Wang
Zainab Al-taie
Jerome Martin
Huaibin M. Ko
Minami Tokuyama
Michael Tankelevich
Hadar Meringer
Francesca Cossarini
Divya Jha
Azra Krek
John D. Paulsen
M. Zuber Nakadar
Joshua Wong
Emma C. Erlich
Emily J. Onufer
Beth A. Helmink
Keshav Sharma
Adam Rosenstein
Grace Chung
Travis Dawson
Julius Juarez
Vijay Yajnik
Andrea Cerutti
Jeremiah Faith
Mayte Suarez-Farinas
Carmen Argmann
Francesca Petralia
Gwendalyn J. Randolph
Alexandros D. Polydorides
Andrea Reboldi
Jean Frederic Colombel
Saurabh Mehandru
Publication Year :
2023
Publisher :
Cold Spring Harbor Laboratory, 2023.

Abstract

Targeting the α4β7-MAdCAM-1 axis with vedolizumab (VDZ) is a front-line therapeutic paradigm in ulcerative colitis (UC). However, mechanism(s) of action (MOA) of VDZ remain relatively undefined. Here, we examined three distinct cohorts of patients with UC (n=83, n=60, and n=21), to determine the effect of VDZ on the mucosal and peripheral immune system. Transcriptomic studies with protein level validation were used to study drug MOA using conventional and transgenic murine models. We found a significant decrease in colonic and ileal naïve B and T cells and circulating gut-homing plasmablasts (β7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyer’s patches (PP) demonstrated a significant loss cellularity associated with reduction in follicular B cells, including a unique population of epithelium-associated B cells, following anti-α4β7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-α4β7 mAb treated mice. In VDZ-treated, but not anti-tumor necrosis factor-treated UC patients, lymphoid aggregate size was significantly reduced in treatment responders compared to non-responders, with an independent validation cohort further confirming these data. GALT targeting represents a novel MOA of α4β7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.

Details

Database :
OpenAIRE
Accession number :
edsair.doi...........92ff07021d0101ac12261680dd1e33b7
Full Text :
https://doi.org/10.1101/2023.01.19.524731