A well-characterized mechanistic model for exploring known or hypothesized T cell mediated drug induced liver injury: current capabilities and challenges for future predictivity
Year: 2025
Type: article
Abstract: Background Drug-induced liver injury (DILI) is an adverse event whose emergence can slow or halt drug development programs. Adaptive immune responses have been implicated for several DILI compounds, and drug-specific T cell responses have been characterized, but there are still many unknowns. We describe the extension of a quantitative systems toxicology (QST) model of DILI to include CD8+ T cell-mediated DILI.Research design and methods To overcome deficits in quantitative data characterizing CD8+ T cell-mediated DILI, a translational strategy leveraged a well-defined mouse ovalbumin (OVA) antigen model and adapted it to represent mouse amodiaquine (AQ)-specific CD8+ T cell-mediated DILI, with further adaptations to represent human AQ-specific CD8+ T cell-mediated DILI.Results DILIsym reproduced published data characterizing mouse OVA-specific CD8+ T cell-mediated hepatotoxicity, mouse AQ-specific CD8+ T cell-mediated DILI, and human AQ-specific CD8+ T cell-mediated DILI. Development identified main drivers of the CD8+ T cell response, as well as areas where in vitro assay data could inform the simulation of additional compounds.Conclusions The DILIsym CD8+ T cell sub-model is well-positioned for systematic testing to improve our understanding of CD8+ T cell-mediated DILI. It is not yet predictive but indicates a promising direction to reduce DILI events in drug development.
Institution: Simulations Plus (United States)
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
OpenAlex ID: W4410086137