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 Krek; John 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

doi:10.1126/sciimmunol.adg7549

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 journal › Article › peer-review

6 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 language	English (US)
Article number	eadg7549
Journal	Science Immunology
Volume	9
Issue number	94
DOIs	https://doi.org/10.1126/sciimmunol.adg7549
State	Published - Apr 2024
Externally published	Yes

ASJC Scopus subject areas

Immunology and Allergy
Immunology

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Canales-Herrerias, P., Uzzan, M., Seki, A., Czepielewski, R. S., Verstockt, B., Livanos, A. E., Raso, F., Dunn, A., Dai, D., Wang, A., Al-Taie, Z., Martin, J., Laurent, T., Ko, H. M., Tokuyama, M., Tankelevich, M., Meringer, H., Cossarini, F., Jha, D., ... Mehandru, S. (2024). Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis. Science Immunology, 9(94), Article eadg7549. https://doi.org/10.1126/sciimmunol.adg7549

Canales-Herrerias, P, Uzzan, M, Seki, A, Czepielewski, RS, Verstockt, B, Livanos, AE, Raso, F, Dunn, A, Dai, D, Wang, A, Al-Taie, Z, Martin, J, Laurent, T, Ko, HM, Tokuyama, M, Tankelevich, M, Meringer, H, Cossarini, F, Jha, D, Krek, A, Paulsen, JD, Taylor, MD, Nakadar, MZ, Wong, J, Erlich, EC, Mintz, RL, Onufer, EJ, Helmink, BA, Sharma, K, Rosenstein, A, Ganjian, D, Chung, G, Dawson, T, Juarez, J, Yajnik, V, Cerutti, A, Faith, JJ, Suarez-Farinas, M, Argmann, C, Petralia, F, Randolph, GJ, Polydorides, AD, Reboldi, A, Colombel, JF & Mehandru, S 2024, 'Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis', Science Immunology, vol. 9, no. 94, eadg7549. https://doi.org/10.1126/sciimmunol.adg7549

@article{61aeab968be04f8da45a8ec597f3106b,

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

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 na{\"i}ve 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.",

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

year = "2024",

month = apr,

doi = "10.1126/sciimmunol.adg7549",

language = "English (US)",

volume = "9",

journal = "Science Immunology",

issn = "2470-9468",

publisher = "American Association for the Advancement of Science",

number = "94",

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TY - JOUR

T1 - Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis

AU - Canales-Herrerias, Pablo

AU - Uzzan, Mathieu

AU - Seki, Akihiro

AU - Czepielewski, Rafael S.

AU - Verstockt, Bram

AU - Livanos, Alexandra E.

AU - Raso, Fiona

AU - Dunn, Alexandra

AU - Dai, Daniel

AU - Wang, Andrew

AU - Al-Taie, Zainab

AU - Martin, Jerome

AU - Laurent, Thomas

AU - Ko, Huaibin M.

AU - Tokuyama, Minami

AU - Tankelevich, Michael

AU - Meringer, Hadar

AU - Cossarini, Francesca

AU - Jha, Divya

AU - Krek, Azra

AU - Paulsen, John D.

AU - Taylor, Matthew D.

AU - Nakadar, Mohammad Zuber

AU - Wong, Joshua

AU - Erlich, Emma C.

AU - Mintz, Rachel L.

AU - Onufer, Emily J.

AU - Helmink, Beth A.

AU - Sharma, Keshav

AU - Rosenstein, Adam

AU - Ganjian, Danielle

AU - Chung, Grace

AU - Dawson, Travis

AU - Juarez, Julius

AU - Yajnik, Vijay

AU - Cerutti, Andrea

AU - Faith, Jeremiah J.

AU - Suarez-Farinas, Mayte

AU - Argmann, Carmen

AU - Petralia, Francesca

AU - Randolph, Gwendalyn J.

AU - Polydorides, Alexandros D.

AU - Reboldi, Andrea

AU - Colombel, Jean Frederic

AU - Mehandru, Saurabh

PY - 2024/4

Y1 - 2024/4

N2 - 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.

AB - 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.

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U2 - 10.1126/sciimmunol.adg7549

DO - 10.1126/sciimmunol.adg7549

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AN - SCOPUS:85191104135

SN - 2470-9468

VL - 9

JO - Science Immunology

JF - Science Immunology

IS - 94

M1 - eadg7549

ER -

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

Abstract

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