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PubMed · 42567373

Utility of monocyte-derived cells to investigate immune-mediated drug-induced liver injury.

Monique Ulepic·Maria F Vargas·Stuart Astbury·Magdalena Rausch·Sibylle Pfammatter·Sophia L Samodelov·Jane I Grove·Gerd A Kullak-Ublick·Nicholas R F Hannan·Guruprasad P Aithal·Michele Visentin
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Abstract

Immune-mediated drug-induced liver injury (DILI) is triggered or exacerbated by the immune system mounting an attack against the drug or its metabolites. The array of in vitro assays for evaluating drug immune liability is limited, highlighting a significant gap in effectively predicting and understanding immune-mediated hepatotoxicity. We aimed to investigate whether monocytes differentiated with the Metaheps (MH) protocol could provide insights into the molecular mechanisms of immune-mediated DILI. MH were generated from monocytes of healthy volunteers (HV) and DILI patients. MH phenotypic characterization was performed by proteomics and qPCR. MH sensitivity to drugs associated with immune-mediated DILI was assessed by lactate dehydrogenase (LDH) assay. Drug-induced LDH release by DILI-derived MH was compared to the upper limit of the 95% CI calculated from HV-derived MH cells treated with the same drug. The 95% CI determined in HV-derived MH was set as the sensitivity threshold for the specific drug. MH cells retain the expression of several immune-related proteins of the parental monocytes and activate a pro-inflammatory response upon exposure to lipopolysaccharide. For all MH (6 out of 6) generated from patients with penicillin-induced DILI, the LDH release upon re-challenge was above the threshold. The sensitivity of MH generated from seven patients with immune checkpoint inhibitor (ICI)-induced hepatotoxicity was ICI-dependent, responding to nivolumab and/or ipilimumab (4 out of 5), but not to pembrolizumab (0 out of 2). Additionally, DILI-derived MH were not sensitive to non-DILI drugs. In conclusion, monocyte-derived cells may serve as an additional tool for drug-specific mechanistic studies of immune-mediated DILI.

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HumansChemical and Drug Induced Liver InjuryMonocytesL-Lactate DehydrogenaseImmune Checkpoint InhibitorsFemaleMaleProteomicsCells, CulturedAmoxicillin-ClavulanateDILIDrug-induced liver injuryFlucloxacillinMetaHepsJournal Article

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Monique Ulepic, Maria F Vargas, Stuart Astbury, Magdalena Rausch, Sibylle Pfammatter, Sophia L Samodelov, Jane I Grove, Gerd A Kullak-Ublick, Nicholas R F Hannan, Guruprasad P Aithal, Michele Visentin. 2026-08-07. Utility of monocyte-derived cells to investigate immune-mediated drug-induced liver injury.. https://doi.org/10.1016/j.toxlet.2026.113176

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Journal Article resourceCells, Cultured subjectFemale subjectHumans subjectImmune Checkpoint Inhibitors subjectJournal Article subjectMale subject

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