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Updated: Jun 9, 2026
Induction of Drug-Induced, Autoimmune Hepatitis in BALB/c Mice for the Study of Its Pathogenic Mechanisms
Published on: May 29, 2020
A well-characterized mechanistic model for exploring known or hypothesized T cell mediated drug induced liver injury:
Lara Clemens1, Christina Battista1, Zackary R Kenz1
1QSP Solutions, Simulations Plus, Inc., Research Triangle Park, NC, USA.
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.
Insights
Quantitative systems toxicology modeling now includes CD8+ T cell-mediated drug-induced liver injury (DILI). This approach successfully reproduced DILI data in mouse and human models, offering a promising direction for reducing DILI in drug development.
Area of Science:
- * Toxicology and Pharmacology
- * Computational Biology and Systems Toxicology
Background:
- * Drug-induced liver injury (DILI) poses a significant challenge in drug development, often linked to adaptive immune responses.
- * While drug-specific T cell responses are implicated, a comprehensive understanding of CD8+ T cell-mediated DILI remains incomplete.
Purpose of the Study:
- * To extend a quantitative systems toxicology (QST) model of DILI to incorporate CD8+ T cell-mediated mechanisms.
- * To address limitations in quantitative data for CD8+ T cell-mediated DILI through a translational modeling strategy.
Main Methods:
- * A translational strategy adapted a mouse ovalbumin (OVA) model to represent amodiaquine (AQ)-specific CD8+ T cell-mediated DILI in mice.
- * Further adaptations were made to model human AQ-specific CD8+ T cell-mediated DILI using the DILIsym platform.
Main Results:
- * The DILIsym model accurately reproduced published data for mouse OVA-specific CD8+ T cell-mediated hepatotoxicity.
- * The model successfully simulated mouse and human AQ-specific CD8+ T cell-mediated DILI.
- * Key drivers of the CD8+ T cell response were identified, highlighting areas for future *in vitro* data integration.
Conclusions:
- * The DILIsym CD8+ T cell sub-model provides a framework for systematic investigation of CD8+ T cell-mediated DILI.
- * While not yet predictive, the model represents a promising advancement for mitigating DILI during drug development.
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