Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease

Bingbing Dai, Jason A. Hackney, Ryan Ichikawa, Allen Nguyen, Justin Elstrott, Luz D. Orozco, Kai Hui Sun, Zora Modrusan, Alvin Gogineni, Alexis Scherl, John Gubatan, Aida Habtezion, Monika Deswal, Ma Somsouk, William A. Faubion, Akiko Chai, Zaineb Sharafali, Azra Hassanali, Young S. Oh, Swati ToleJacqueline McBride, Mary E. Keir, Tangsheng Yi

Research output: Contribution to journalArticlepeer-review

Abstract

Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of α4β7 and αEβ7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of α4β7 and αEβ7 blockade using a combination of murine models of gut trafficking and longitudinal gene expression analysis in etrolizumab-treated patients with Crohn's disease (CD). Dual blockade of α4β7 and αEβ7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-αEβ7 reduces epithelial:T cell interactions and promotes egress of activated T cells from the mucosa into lymphatics. Inflammatory gene expression is greater in human intestinal αEβ7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of α4β7 and αEβ7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention.

Original languageEnglish (US)
Article number100381
JournalCell Reports Medicine
Volume2
Issue number8
DOIs
StatePublished - Aug 17 2021

Keywords

  • etrolizumab
  • inflammatory bowel disease
  • T cell entry and retention
  • α4β7
  • αEβ7

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

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