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

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 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.

Using fluorescently labeled vedolizumab to visualize local drug distribution during colonoscopy and identify mucosal target cells in patients with inflammatory bowel disease

“…Specifically, our fluorescence microscopic analysis revealed both surface and intracellular vedo-800CW binding. In addition, consistent with recent findings 14,17,19 we found that vedolizumab binds to a variety of immune cell types, including plasma cells, macrophages, and eosinophils whereas an actual correlation between T cells and vedo-800CW was not observed. These findings support the hypothesis that T cell migration to the mucosa is prevented and that T cells are likely not the sole therapeutic target of vedolizumab.…”

“…With respect to vedolizumab, whether cells other than T cells play a role in its mechanism of action remains an open question. 14,19 Here, we show that not only is vedo-800CW distributed in a dose-dependent manner in the inflamed mucosa, but it also binds to and/or is taken up by a variety of immune cell types.…”

“…28 Moreover, Canales-Herrerias et al recently reported in a preprint that vedolizumab can affect the abundance of mucosal plasma cells. 10,19 Nevertheless, vedolizumab was shown to have opposite effects on the abundance of specific plasma cell subtypes, increasing some subtypes but decreasing others. 10,19 Here, we found intracellular localization of vedolizumab in both macrophages and eosinophils, consistent with previous studies showing an interaction between vedolizumab and α4β7expressing macrophages and eosinophils.…”

“…10,19 Nevertheless, vedolizumab was shown to have opposite effects on the abundance of specific plasma cell subtypes, increasing some subtypes but decreasing others. 10,19 Here, we found intracellular localization of vedolizumab in both macrophages and eosinophils, consistent with previous studies showing an interaction between vedolizumab and α4β7expressing macrophages and eosinophils. 12,17,29 Although this interaction between vedolizumab and various immune cell types is well established, the consequences of this drug binding to different immune cell types remain poorly understood and require further study.…”

“…[8][9][10] In contrast, recent studies suggest that a wide range of α4β7-expressing immune cells may be involved in mediating vedolizumab's anti-inflammatory effects. [11][12][13][14][15][16][17][18][19] However, none of these experimental studies directly visualized the tissue distribution of vedolizumab or its interaction with target cells in the inflamed gut mucosa.…”