Selective Targeting of α4β7/MAdCAM-1 Axis Suppresses Fibrosis Progression by Reducing Proinflammatory T Cell Recruitment to the Liver

Integrin alpha(4)beta(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 alpha(4)beta(7)+ 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 alpha(4)beta(7)+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of alpha(4)beta(7) 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 alpha(4)beta(7)+ CD4 and CD8 T cells, suggesting that alpha(4)beta(7)/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and alpha(4)beta(7 )+ T cells promote hepatic fibrosis progression. Analysis of hepatic alpha(4)beta(7 )+ and alpha(4)beta(7)- CD4 T cells revealed that alpha(4)beta(7)+ CD4 T cells were enriched for markers of activation and proliferation, demonstrating an effector phenotype. The findings suggest that alpha(4)beta(7)+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of alpha(4)beta(7) or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.