Dual targeting of lymphocyte homing and retention through a4ß7 and aEß7 inhibition in inflammatory bowel disease.

Dual targeting of lymphocyte homing and retention through a4ß7 and aEß7 inhibition in inflammatory bowel disease. Cell reports. Medicine 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., Tole, S., McBride, J., Keir, M. E., Yi, T. 2021; 2 (8): 100381

Abstract

Anti-integrins are therapeutically effective for inflammatory bowel disease, yet the relative contribution of a4ß7 and aEß7 to gut lymphocyte trafficking is not fully elucidated. Here, we evaluate the effect of a4ß7 and aEß7 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 a4ß7 and aEß7 reduces CD8+ T cell accumulation in the gut to a greater extent than blockade of either integrin alone. Anti-aEß7 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 aEß7+ T cells. Etrolizumab-treated patients with CD display a treatment-specific reduction in inflammatory and cytotoxic intraepithelial lymphocytes (IEL) genes. Concurrent blockade of a4ß7 and aEß7 promotes reduction of cytotoxic IELs and inflammatory T cells in the gut mucosa through a stepwise inhibition of intestinal tissue entry and retention.

View details for DOI 10.1016/j.xcrm.2021.100381

View details for PubMedID 34467254

View details for PubMedCentralID PMC8385326