In:
Toxicological Sciences, Oxford University Press (OUP), ( 2023-10-03)
Kurzfassung:
In vitro preclinical drug-induced liver injury (DILI) risk assessment relies largely on use of hepatocytes to measure drug-specific changes in cell function or viability. Unfortunately, this does not provide indications towards the immunogenicity of drugs and/or the likelihood for 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 utilised immune cells from drug-naïve donors, recently established immune cell co-culture 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 five 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 co-culture; however, CD4+ clones displaying reactivity were detected towards 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.
Materialart:
Online-Ressource
ISSN:
1096-6080
,
1096-0929
DOI:
10.1093/toxsci/kfad101
Sprache:
Englisch
Verlag:
Oxford University Press (OUP)
Publikationsdatum:
2023
ZDB Id:
1471974-5
