244: Vedolizumab Reduces Dendritic Cells and Naïve Lymphocytes in the Colon Mucosa

Lord, James D.; Kongala, Ramya; Juarez, Julius

doi:10.1016/s0016-5085(22)60124-0

Cited by 2 publications

(1 citation statement)

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“…We tested our hypothesis in murine studies using multiple orthogonal experimental approaches and observed a highly significant attenuation of lymphoid structures following anti-α4β7 antibody administration, which was unequivocally associated with impaired entry of follicular naïve B cells and naïve T cells. Our data does not exclude some of the other suggested VDZ effects on intestinal and circulating immune cells that include reduced frequencies of mucosal DCs 41 and a preferential inhibition of effector T cell migration over inhibition of T REG migration 42 .…”

Section: Discussioncontrasting

confidence: 79%

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

Canales-Herrerías

Uzzan

Seki

et al. 2023

Preprint

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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 naive 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.

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Section: Discussioncontrasting

confidence: 79%