T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury.

Wuillemin, Natascha Andrea; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner Joseph; Yerly, Daniel (2014). T cells infiltrate the liver and kill hepatocytes in HLA-B(∗)57:01-associated floxacillin-induced liver injury. American journal of pathology, 184(6), pp. 1677-1682. Elsevier 10.1016/j.ajpath.2014.02.018

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Rheumatology, Clinical Immunology and Allergology
04 Faculty of Medicine > Department of Haematology, Oncology, Infectious Diseases, Laboratory Medicine and Hospital Pharmacy (DOLS) > Clinic of Haematology and Central Haematological Laboratory
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Nephrology and Hypertension
04 Faculty of Medicine > Department of Dermatology, Urology, Rheumatology, Nephrology, Osteoporosis (DURN) > Clinic of Dermatology
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Wuillemin, Natascha Andrea; Terracciano, Luigi; Beltraminelli, Helmut; Schlapbach, Christoph; Fontana, Stefano; Krähenbühl, Stephan; Pichler, Werner Joseph and Yerly, Daniel

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0002-9440

Publisher:

Elsevier

Language:

English

Submitter:

Monika Schenk

Date Deposited:

16 Apr 2015 15:06

Last Modified:

16 Apr 2015 15:06

Publisher DOI:

10.1016/j.ajpath.2014.02.018

PubMed ID:

24731753

BORIS DOI:

10.7892/boris.60537

URI:

https://boris.unibe.ch/id/eprint/60537

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