Mechanistic mathematical representation of CD8+ T cell mediated drug-induced liver injury (DILI) Part 3: translation from mouse to human amodiaquine (AQ) response

• Published in: The Journal of immunology (1950) 2020-05, Vol.204 (1_Supplement), p.72-72.9
• Main Authors: Shoda, Lisl, Battista, Christina, Kenz, Zackary
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.204.Supp.72.9

Idiosyncratic DILI (iDILI) is poorly understood and costly to patients and drug developers. Some iDILI events appear immune-mediated. This work builds on DILIsym mouse modeling of CD8+ T cell mediated killing of OVA or AQ-expressing hepatocytes1,2 to develop a human representation of AQ DILI. The representation was adapted to account for human AQ exposure and endogenous T cell numbers3,4. Simulation results indicate an adult human treated with 200–700 mg AQ weekly is unlikely to present with liver injury, even if liver tolerance is broken. Simulations reflect alternate mechanisms of non-response depending on antigen levels. With low antigen, few responsive T cells of low affinity and avidity result in low level expansion without effective cytotoxicity. At high antigen levels, the emergent T cell response is dominated by dysfunctional T cells (exhaustion). However, when regulatory pathways (co-inhibition, exhaustion) are perturbed, simulated human liver injury manifests over weeks to months consistent with case reports5. Halting treatment led to simulated recovery provided sufficient liver mass remained; subsequent AQ re-challenge resulted in a more rapid ALT response, consistent with data5, mechanistically mediated by re-activation of memory T cells. Simulation results provide proof-of-concept that CD8+ T cell mediated cytotoxicity can explain human AQ DILI. Evaluation of additional compounds and the identification of testable experimental hypotheses are needed to demonstrate model utility in understanding iDILI.