May 2026: Innate and Adaptive Immunity in iDILI-Innate and adaptive immune activation in iDILI

Video Transcription

Video Summary

The seminar introduced Dr. Jack Uetrecht, a leading expert in idiosyncratic drug-induced liver injury (iDILI). He discussed the challenges of predicting iDILI, which is rare, delayed, often immune-mediated, and costly for drug development.<br /><br />Uetrecht argued that common ideas like simple cytotoxicity, LPS stimulation, mitochondrial electron transport inhibition, and covalent binding alone do not adequately explain iDILI risk. Instead, he emphasized that most evidence points to an adaptive immune response, especially CD8 T cells, with HLA associations, viral-hepatitis-like histology, and immune-related biomarkers supporting this view.<br /><br />He outlined a model in which a drug or reactive metabolite first activates antigen-presenting cells through innate immune “signal 2,” then drives CD8 T-cell activation and hepatocyte killing. He presented animal and cell studies showing early inflammatory signals, adaptation/immune tolerance with continued dosing, and protective effects from low-dose escalation. He also described biomarker work involving cytokines, stress-response genes, inflammasome activation, and possible extracellular vesicles.<br /><br />In Q&A, he discussed the microbiome, inflammatory bowel disease, and deuterium substitution in drug metabolism. He concluded that mechanism-based biomarkers and early innate immune responses may eventually improve prediction of iDILI during drug development.

Keywords

idiosyncratic drug-induced liver injury

iDILI

Dr. Jack Uetrecht

adaptive immune response

CD8 T cells

HLA associations

innate immune signaling

biomarkers

drug development