TY - JOUR
KW - CD8⁺ T cells
KW - HLA‐B*57:01
KW - immune‐mediated toxicity
KW - liver organoids
KW - organoid‐immune co‐culture platforms
AU - Fadoua El Abdellaoui Soussi
AU - Michael Brusilovsky
AU - Emma Buck
AU - W. Clark Bacon
AU - Sina Dadgar
AU - Aaron Fullerton
AU - Victoria Marsh Durban
AU - Riccardo Barrile
AU - Michael A. Helmrath
AU - Takanori Takebe
AU - Adrian Roth
AU - Magdalena Kasendra
AB - Modeling adaptive immune responses in induced pluripotent stem cell (iPSC)-derived liver systems remains a critical barrier for studying immune-mediated hepatic diseases, including idiosyncratic drug-induced liver injury (iDILI). Conventional hepatotoxicity models lack the components required to capture patient-specific, T cell-mediated injury. Here, a scalable and matrix-free human liver organoid (HLO) microarray platform is presented that enables controlled co-culture of Human Leukocyte Antigen (HLA)-genotyped, iPSC-derived HLOs with autologous CD8⁺ T cells. This immune-competent system supports antigen-specific T cell activation and reproduces cytotoxic effector responses in a genetically defined context. As a proof-of-concept, the platform models clinically relevant iDILI caused by flucloxacillin in HLA-B*57:01 carriers, recapitulating CD8⁺ T cell proliferation, hepatocyte apoptosis, and variability in immune responses across donors. The system captures hallmark features of adaptive immune-mediated hepatotoxicity, including secretion of tumor necrosis factor-alpha and Granzyme B, and cytokeratin-18 release from injured hepatocytes. By linking genetic susceptibility with functional immune outcomes, this platform provides a modular and scalable approach for evaluating immune-mediated toxicities. The method offers broad utility for mechanistic studies of drug hypersensitivity, immune-related adverse events, and preclinical safety assessment in support of precision medicine.
BT - Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
DA - 2025-09-26
DO - 10.1002/advs.202508584
LA - eng
N2 - Modeling adaptive immune responses in induced pluripotent stem cell (iPSC)-derived liver systems remains a critical barrier for studying immune-mediated hepatic diseases, including idiosyncratic drug-induced liver injury (iDILI). Conventional hepatotoxicity models lack the components required to capture patient-specific, T cell-mediated injury. Here, a scalable and matrix-free human liver organoid (HLO) microarray platform is presented that enables controlled co-culture of Human Leukocyte Antigen (HLA)-genotyped, iPSC-derived HLOs with autologous CD8⁺ T cells. This immune-competent system supports antigen-specific T cell activation and reproduces cytotoxic effector responses in a genetically defined context. As a proof-of-concept, the platform models clinically relevant iDILI caused by flucloxacillin in HLA-B*57:01 carriers, recapitulating CD8⁺ T cell proliferation, hepatocyte apoptosis, and variability in immune responses across donors. The system captures hallmark features of adaptive immune-mediated hepatotoxicity, including secretion of tumor necrosis factor-alpha and Granzyme B, and cytokeratin-18 release from injured hepatocytes. By linking genetic susceptibility with functional immune outcomes, this platform provides a modular and scalable approach for evaluating immune-mediated toxicities. The method offers broad utility for mechanistic studies of drug hypersensitivity, immune-related adverse events, and preclinical safety assessment in support of precision medicine.
PY - 2025
EP - e08584
T2 - Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
TI - Autologous Organoid-T Cell Co-Culture Platform for Modeling of Immune-Mediated Drug-Induced Liver Injury
SN - 2198-3844
ER -