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

Canales-Herrerias, P.; Uzzan, M.; Seki, A.; Czepielewski, R. S.; Verstockt, B.; Livanos, A.; Raso, F.; Dunn, A.; Dai, D.; Wang, A.; Al-taie, Z.; Martin, J.; Ko, H. M.; Tokuyama, M.; Tankelevich, M.; Meringer, H.; Cossarini, F.; Jha, D.; Krek, A.; Paulsen, J. D.; Zuber Nakadar, M.; Wong, J.; Erlich, E. C.; Onufer, E. J.; Helmink, B. A.; Sharma, K.; Rosenstein, A.; Chung, G.; Dawson, T.; Juarez, J.; Yajnik, V.; Cerutti, A.; Faith, J.; Suarez-Farinas, M.; Argmann, C.; Petralia, F.; Randolph, G. J.; Polydorides, A. D.; Reboldi, A.; Colombel, J. F.; Mehandru, S.

doi:10.1101/2023.01.19.524731

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bioRxiv · 10.1101/2023.01.19.524731

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

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Abstract

Targeting the 4{beta}7-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 ({beta}7+) in VDZ-treated patients, pointing to gut-associated lymphoid tissue (GALT) targeting by VDZ. Murine Peyers 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-4{beta}7 antibody (mAb) administration. Photoconvertible (KikGR) mice unequivocally demonstrated impaired cellular entry into PPs in anti-4{beta}7 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 4{beta}7-targeted therapies, with major implications for this therapeutic paradigm in UC, and for the development of new therapeutic strategies.

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Canales-Herrerias, P., Uzzan, M., Seki, A., Czepielewski, R. S., Verstockt, B., Livanos, A., Raso, F., Dunn, A., Dai, D., Wang, A., Al-taie, Z., Martin, J., Ko, H. M., Tokuyama, M., Tankelevich, M., Meringer, H., Cossarini, F., Jha, D., Krek, A., Paulsen, J. D., Zuber Nakadar, M., Wong, J., Erlich, E. C., Onufer, E. J., Helmink, B. A., Sharma, K., Rosenstein, A., Chung, G., Dawson, T., Juarez, J., Yajnik, V., Cerutti, A., Faith, J., Suarez-Farinas, M., Argmann, C., Petralia, F., Randolph, G. J., Polydorides, A. D., Reboldi, A., Colombel, J. F., Mehandru, S.. 2023-01-20. Gut-associated lymphoid tissue attrition associates with response to anti-α4β7 therapy in ulcerative colitis. https://doi.org/10.1101/2023.01.19.524731

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