Modeling adaptive immune reactions in vitro is a significant gap in liver research and drug development. Immune-mediated liver injuries like drug hypersensitivity, autoimmune hepatitis, and immune-related adverse effects from cancer immunotherapy are caused by complicated and patient-specific mechanisms. Current preclinical processes cannot be reproduced. Idiosyncratic drug-induced liver injury (iDILI) represents a major clinical and regulatory concern, as it is a leading cause of drug withdrawals and safety warnings. It also accounts for a significant proportion of acute liver failure cases unrelated to overdose.
Current in vitro methods can not mimic the Human Leukocyte Antigen (HLA)-restricted, cytotoxic CD8⁺ T-cell responses that mediate the immune-specific hepatocyte injury that leads to translational gap stems. Advances like induced pluripotent stem cell (iPSC)-derived hepatocytes and the liver-on-chip method have enhanced the physiological fidelity of hepatic metabolism and innate immune signaling. However, it still fails to replicate the adaptive immune pathways that are crucial for accurately modeling immune-mediated hepatotoxicity.
The aim of this study was to develop and validate a fully human and matrix-free liver organoid (HLO) microarray platform, which integrated iPSC-derived hepatocytes with the autologous CD8⁺ T cells in a genetically defined context. It also established a scalable and reproducible co-culture system, which is capable of modeling the antigen-specific immune reaction and immune-mediated hepatotoxicity. It bridges the gap in functional immune response and genetic susceptibility in iDILI.
Reference
Soussi FEA, Brusilovsky M, Buck E, et al. Autologous organoid–T cell co-culture platform for modeling of immune-mediated drug-induced liver injury. Adv Sci. 2025; e08584. doi:10.1002/advs.202508584
