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Journal article
A blinded in vitro analysis of the intrinsic immunogenicity of hepatotoxic drugs: implications for preclinical risk assessment
Toxicological sciences, Vol.197(1), pp.38-52
2023
Abstract
In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on the use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications toward the immunogenicity of drugs and/or the likelihood of idiosyncratic reactions in the clinic. This is because the molecular initiating event in immune DILI is an interaction of the drug-derived antigen with MHC proteins and the T-cell receptor. This study utilized immune cells from drug-naïve donors, recently established immune cell coculture systems and blinded compounds with and without DILI liabilities to determine whether these new methods offer an improvement over established assessment methods for the prediction of immune-mediated DILI. Ten blinded test compounds (6 with known DILI liabilities; 4 with lower DILI liabilities) and 5 training compounds, with known T-cell-mediated immune reactions in patients, were investigated. Naïve T-cells were activated with 4/5 of the training compounds (nitroso sulfamethoxazole, vancomycin, Bandrowski’s base, and carbamazepine) and clones derived from the priming assays were activated with drug in a dose-dependent manner. The test compounds with DILI liabilities did not stimulate T-cell proliferative responses during dendritic cell-T-cell coculture; however, CD4+ clones displaying reactivity were detected toward 2 compounds (ciprofloxacin and erythromycin) with known liabilities. Drug-responsive T-cells were not detected with the compounds with lower DILI liabilities. This study provides compelling evidence that assessment of intrinsic drug immunogenicity, although complex, can provide valuable information regarding immune liabilities of some compounds prior to clinical studies or when immune reactions are observed in patients.
Details
- Title
- A blinded in vitro analysis of the intrinsic immunogenicity of hepatotoxic drugs: implications for preclinical risk assessment
- Authors/Creators
- Monday O Ogese - University of LiverpoolAdam Lister - University of LiverpoolLiam Farrell - University of LiverpoolJoshua Gardner - University of LiverpoolLaila Kafu - University of LiverpoolSerat-E Ali - University of LiverpoolAndrew Gibson - Murdoch University, Centre for Molecular Medicine and Innovative TherapeuticsAimee Hillegas - GlaxoSmithKlineXiaoli Meng - University of LiverpoolMunir Pirmohamed - University of LiverpoolGeoffrey S WilliamsMelanie Z Sakatis - University of HertfordshireDean J Naisbitt - University of Liverpool
- Publication Details
- Toxicological sciences, Vol.197(1), pp.38-52
- Publisher
- Oxford University Press on behalf of the Society of Toxicology
- Identifiers
- 991005609667007891
- Copyright
- © 2023 The Author(s).
- Murdoch Affiliation
- Institute for Immunology and Infectious Diseases
- Language
- English
- Resource Type
- Journal article
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- 1.265 Dermatology - Skin Allergies
- 1.265.1140 Drug Hypersensitivity
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