title: T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.
abstract: Drug-induced liver injury is a major safety issue. It can cause severe disease and is a common cause of the withdrawal of drugs from the pharmaceutical market. Recent studies have identified the HLA-B(∗)57:01 allele as a risk factor for floxacillin (FLUX)-induced liver injury and have suggested a role for cytotoxic CD8(+) T cells in the pathomechanism of liver injury caused by FLUX. This study aimed to confirm the importance of FLUX-reacting cytotoxic lymphocytes in the pathomechanism of liver injury and to dissect the involved mechanisms of cytotoxicity. IHC staining of a liver biopsy from a patient with FLUX-induced liver injury revealed periportal inflammation and the infiltration of cytotoxic CD3(+) CD8(+) lymphocytes into the liver. The infiltration of cytotoxic lymphocytes into the liver of a patient with FLUX-induced liver injury demonstrates the importance of FLUX-reacting T cells in the underlying pathomechanism. Cytotoxicity of FLUX-reacting T cells from 10 HLA-B(∗)57:01(+) healthy donors toward autologous target cells and HLA-B(∗)57:01-transduced hepatocytes was analyzed in vitro. Cytotoxicity of FLUX-reacting T cells was concentration dependent and required concentrations in the range of peak serum levels after FLUX administration. Killing of target cells was mediated by different cytotoxic mechanisms. Our findings emphasize the role of the adaptive immune system and especially of activated drug-reacting T cells in human leukocyte antigen-associated, drug-induced liver injury.
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland.
authors.forename: Natascha
authors.initials: N
authors.lastname: Wuillemin
authors.affiliation: Division of Molecular Pathology Division, Institute of Pathology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.affiliation: Department of Dermatology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Helmut
authors.initials: H
authors.lastname: Beltraminelli
authors.affiliation: Department of Dermatology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Christoph
authors.initials: C
authors.lastname: Schlapbach
authors.affiliation: Regional Blood Transfusion Service, Swiss Red Cross, Bern, Switzerland.
authors.forename: Stefano
authors.initials: S
authors.lastname: Fontana
authors.affiliation: Division of Clinical Pharmacology and Toxicology, University Hospital of Basel, Basel, Switzerland.
authors.forename: Stephan
authors.initials: S
authors.lastname: Krähenbühl
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland. Electronic address: werner.pichler@insel.ch.
authors.forename: Werner J
authors.initials: WJ
authors.lastname: Pichler
authors.affiliation: Clinic for Rheumatology and Clinical Immunology/Allergology, University Hospital of Bern, Bern, Switzerland.
authors.forename: Daniel
authors.initials: D
authors.lastname: Yerly
mesh_terms: D000900:Anti-Bacterial Agents / Q000009:adverse effects* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes; D002460:Cell Line; D056486:Chemical and Drug Induced Liver Injury / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005260:Female; D005436:Floxacillin / Q000009:adverse effects* / Q000494:pharmacology; D015235:HLA-B Antigens / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000473:pathology; D006801:Humans; D008099:Liver / Q000276:immunology* / Q000473:pathology; D008297:Male
chemical_list: D000900:Anti-Bacterial Agents; D015235:HLA-B Antigens; C484830:HLA-B*57:01 antigen; D005436:Floxacillin