Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis.
Pablo Canales-HerreriasMathieu UzzanAkihiro SekiRafael S CzepielewskiBram VerstocktAlexandra E LivanosFiona RasoAlexandra DunnDaniel DaiAndrew A WangZainab Al-TaieJerome MartinThomas LaurentHuaibin Mabel KoMinami TokuyamaMichael TankelevichHadar MeringerFrancesca CossariniDivya JhaAzra KrekJohn David PaulsenMatthew D TaylorMohammad Zuber NakadarJoshua WongEmma C ErlichRachel L MintzEmily J OnuferBeth A HelminkKeshav SharmaAdam RosensteinDanielle GanjianGrace ChungTravis DawsonJulius JuarezVijay YajnikAndrea CeruttiJeremiah J FaithMayte Suarez-FarinasCarmen ArgmannFrancesca PetraliaGwendalyn J RandolphAlexandros D PolydoridesAndrea ReboldiJean Frederic ColombelSaurabh MehandruPublished in: Science immunology (2024)
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.