Selective Targeting of α 4 β 7 /MAdCAM-1 Axis Suppresses Fibrosis Progression by Reducing Proinflammatory T Cell Recruitment to the Liver.

Integrin α 4 β 7 + 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 α 4 β 7 + T cells in the liver of people with cirrhosis relative to disease controls. Similarly, hepatic fibrosis in the established mouse model of CCl 4 -induced liver fibrosis was associated with enrichment of intrahepatic α 4 β 7 + CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of α 4 β 7 or its ligand mucosal addressin cell adhesion molecule (MAdCAM)-1 attenuated hepatic inflammation and prevented fibrosis progression in CCl 4 -treated mice. Improvement in liver fibrosis was associated with a significant decrease in the infiltration of α 4 β 7 + CD4 and CD8 T cells, suggesting that α 4 β 7 /MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and α 4 β 7 + T cells promote hepatic fibrosis progression. Analysis of hepatic α 4 β 7 + and α 4 β 7 - CD4 T cells revealed that α 4 β 7 + CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that α 4 β 7 + T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of α 4 β 7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.