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The regulation of T‐cell recruitment to the human liver during acute liver failure
Author(s) -
Tuncer Ceren,
Oo Ye H.,
Murphy Nick,
Adams David H.,
Lalor Patricia F.
Publication year - 2013
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12182
Subject(s) - chemokine , immunology , liver injury , hepatocyte , cell adhesion molecule , lymphocyte , immune system , endothelium , peripheral blood mononuclear cell , biology , in vitro , pharmacology , endocrinology , biochemistry
Background & Aims Acute liver failure ( ALF ) is a rare clinical syndrome with high mortality resulting from hepatocellular necrosis and loss of function. In seronegative hepatitis ( SNH ), a T‐cell‐rich infiltrate leads to immune‐mediated hepatocyte destruction, whereas in paracetamol poisoning, toxic metabolites induce hepatocyte necrosis, followed by a macrophage‐rich, lymphocytic infiltrate that is an important factor in driving repair and regeneration. The nature of the hepatic inflammatory infiltrate, key to ALF pathogenesis and outcome, is determined by the recruitment of effector cells from blood, but the molecular basis of recruitment is poorly understood. To determine the phenotype of circulating and hepatic lymphocytes in patients with ALF secondary to paracetamol overdose ( POD ) or SNH and investigate the molecular basis of lymphocyte recruitment. Methods We used FACS , immunohistochemistry and flow‐based adhesion assays to determine the regulation of lymphocyte adhesion. Results SNH and POD intrahepatic lymphocytes were αLβ2 hi , CD 69 hi and CD 38 hi with a distinct homing phenotype being L‐selectin lo , CXCR 3 hi and CCR 5 + . Expression of chemokine ligands for the receptors CCR 5, CXCR 3 and CXCR 6 and the adhesion molecules ICAM ‐1, VCAM ‐1 and VAP ‐1 was markedly increased in the liver in ALF . Lymphocytes isolated from the livers of patients with SNH showed enhanced chemokine‐dependent adhesion and transmigration across the human hepatic endothelium in vitro under flow and used a combination of β1 and β2 integrins to adhere to endothelium and β2 integrins, CD 31 and VAP ‐1 to transmigrate. Conclusion Aetiology‐dependent combinations of adhesion molecules and chemokines expressed within tissue during ALF recruit lymphocytes with a distinct homing phenotype.