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bioRxiv · 10.1101/2023.02.20.528201

Selective targeting of α4β7/MAdCAM-1 axis suppresses fibrosis progression in chronic liver disease

Gupta, B.·Rai, R. P.·Pal, P. B.·Chaudhary, S.·Chiaro, A.·Seaman, S.·Singhi, A. D.·Monga, S. P.·Iyer, S. S.·Raeman, R.
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Abstract

Integrin 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 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 4{beta}7+ CD4 and CD8 T cells. Monoclonal antibody (mAb)-mediated blockade of 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 4{beta}7+ CD4 and CD8 T cells suggesting that 4{beta}7/MAdCAM-1 axis regulates both CD4 and CD8 T cell recruitment to the fibrotic liver, and 4{beta}7+ T cells promote hepatic fibrosis progression. Analysis of hepatic 4{beta}7+ and 4{beta}7-CD4 T cells revealed that 4{beta}7+ CD4 T cells enriched for markers of activation and proliferation demonstrating an effector phenotype. Notably, blockade of 4{beta}7 or MAdCAM-1 did not affect the recruitment of Foxp3+ regulatory T cells, demonstrating the specificity of 4{beta}7/MAdCAM-1 axis in regulating effector T cell recruitment to the liver. The findings suggest that 4{beta}7+ T cells play a critical role in promoting hepatic fibrosis progression, and mAb-mediated blockade of 4{beta}7 or MAdCAM-1 represents a promising therapeutic strategy for slowing hepatic fibrosis progression in chronic liver diseases.

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Gupta, B., Rai, R. P., Pal, P. B., Chaudhary, S., Chiaro, A., Seaman, S., Singhi, A. D., Monga, S. P., Iyer, S. S., Raeman, R.. 2023-02-21. Selective targeting of α4β7/MAdCAM-1 axis suppresses fibrosis progression in chronic liver disease. https://doi.org/10.1101/2023.02.20.528201

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