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 Tole; Jacqueline McBride; Mary E. Keir; Tangsheng Yi

doi:10.1016/j.xcrm.2021.100381

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 journal › Article › peer-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 language	English (US)
Article number	100381
Journal	Cell Reports Medicine
Volume	2
Issue number	8
DOIs	https://doi.org/10.1016/j.xcrm.2021.100381
State	Published - Aug 17 2021

Keywords

T cell entry and retention
etrolizumab
inflammatory bowel disease
α4β7
αEβ7

ASJC Scopus subject areas

General Biochemistry, Genetics and Molecular Biology

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10.1016/j.xcrm.2021.100381

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Dai, B., Hackney, J. A., Ichikawa, R., Nguyen, A., Elstrott, J., Orozco, L. D., Sun, K. H., Modrusan, Z., Gogineni, A., Scherl, A., Gubatan, J., Habtezion, A., Deswal, M., Somsouk, M., Faubion, W. A., Chai, A., Sharafali, Z., Hassanali, A., Oh, Y. S., ... Yi, T. (2021). Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease. Cell Reports Medicine, 2(8), Article 100381. https://doi.org/10.1016/j.xcrm.2021.100381

Dai, B, Hackney, JA, Ichikawa, R, Nguyen, A, Elstrott, J, Orozco, LD, Sun, KH, Modrusan, Z, Gogineni, A, Scherl, A, Gubatan, J, Habtezion, A, Deswal, M, Somsouk, M, Faubion, WA, Chai, A, Sharafali, Z, Hassanali, A, Oh, YS, Tole, S, McBride, J, Keir, ME & Yi, T 2021, 'Dual targeting of lymphocyte homing and retention through α4β7 and αEβ7 inhibition in inflammatory bowel disease', Cell Reports Medicine, vol. 2, no. 8, 100381. https://doi.org/10.1016/j.xcrm.2021.100381

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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.",

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AU - Dai, Bingbing

AU - Hackney, Jason A.

AU - Ichikawa, Ryan

AU - Nguyen, Allen

AU - Elstrott, Justin

AU - Orozco, Luz D.

AU - Sun, Kai Hui

AU - Modrusan, Zora

AU - Gogineni, Alvin

AU - Scherl, Alexis

AU - Gubatan, John

AU - Habtezion, Aida

AU - Deswal, Monika

AU - Somsouk, Ma

AU - Faubion, William A.

AU - Chai, Akiko

AU - Sharafali, Zaineb

AU - Hassanali, Azra

AU - Oh, Young S.

AU - Tole, Swati

AU - McBride, Jacqueline

AU - Keir, Mary E.

AU - Yi, Tangsheng

PY - 2021/8/17

Y1 - 2021/8/17

N2 - 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.

AB - 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.

KW - T cell entry and retention

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KW - α4β7

KW - αEβ7

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

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Keywords

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