Selective Targeting of α₄β₇/MAdCAM-1 Axis Suppresses Fibrosis Progression by Reducing Proinflammatory T Cell...

Integrin α₄β₇+ T cells perpetuate tissue injury in chronic inflammatory diseases, yet their role in hepatic fibrosis progression remains poorly understood. Here, we report increased accumulation of α₄β₇+ T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl₄-induced liver fibrosis was associated with enrichment of intrahepatic α₄β₇+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α₄β₇ or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl₄-treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α₄β₇+ CD4 and CD8 T cells, suggesting that α₄β₇/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α₄β₇+ T cells promote hepatic fibrosis progression. Analysis of hepatic α₄β₇+ and α₄β₇- CD4 T cells revealed that α₄β₇+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α₄β₇+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α₄β₇ or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.