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- Title
Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis.
- Authors
Canales-Herrerias, Pablo; Uzzan, Mathieu; Seki, Akihiro; Czepielewski, Rafael S.; Verstockt, Bram; Livanos, Alexandra E.; Raso, Fiona; Dunn, Alexandra; Dai, Daniel; Wang, Andrew; Al-taie, Zainab; Martin, Jerome; Laurent, Thomas; Ko, Huaibin M.; Tokuyama, Minami; Tankelevich, Michael; Meringer, Hadar; Cossarini, Francesca; Jha, Divya; Krek, Azra
- 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. Editor's summary: Vedolizumab (VDZ) is a monoclonal antibody that targets the α4β7 integrin and is used to treat ulcerative colitis (UC). Canales-Herrerias et al. examined the mechanism of action of VDZ through the analysis of intestinal biopsies and peripheral blood from patients with UC. They deduced that VDZ targets gut-associated lymphoid tissue (GALT) because VDZ-treated patients had fewer naïve B and T cells in intestinal tissues and decreased circulating β7+ gut-homing plasmablasts, which was validated in anti-α4β7–treated mice. Further analysis of biopsies demonstrated that VDZ treatment response was linked to attenuation of GALT, fewer circulating and intestinal IgG+ plasma cells, and decreased FcγR-dependent signaling. —Christiana Fogg
- Subjects
LYMPHOID tissue; ULCERATIVE colitis; CELL adhesion molecules; PLASMA cells; CIRCULATING tumor DNA; T cells; GENE targeting
- Publication
Science Immunology, 2024, Vol 9, Issue 94, p1
- ISSN
2470-9468
- Publication type
Article
- DOI
10.1126/sciimmunol.adg7549