TY - JOUR T1 - IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept. AU - Roser,Luise A, AU - Sakellariou,Christina, AU - Lindstedt,Malin, AU - Neuhaus,Vanessa, AU - Dehmel,Susann, AU - Sommer,Charline, AU - Raasch,Martin, AU - Flandre,Thierry, AU - Roesener,Sigrid, AU - Hewitt,Philip, AU - Parnham,Michael J, AU - Sewald,Katherina, AU - Schiffmann,Susanne, Y1 - 2024/04/05/ PY - 2024/4/8/medline PY - 2024/4/5/pubmed PY - 2024/4/5/entrez KW - Adverse outcome pathway KW - adverse event KW - drug-induced liver injury KW - hepatotoxicity KW - immune safety KW - immunotherapy KW - interleukin-2 KW - preclinical model SP - 2332177 EP - 2332177 JF - Journal of immunotoxicology JO - J Immunotoxicol VL - 21 IS - 1 N2 - Drug-induced hepatotoxicity constitutes a major reason for non-approval and post-marketing withdrawal of pharmaceuticals. In many cases, preclinical models lack predictive capacity for hepatic damage in humans. A vital concern is the integration of immune system effects in preclinical safety assessment. The immune-related Adverse Outcome Pathway (irAOP) approach, which is applied within the Immune Safety Avatar (imSAVAR) consortium, presents a novel method to understand and predict immune-mediated adverse events elicited by pharmaceuticals and thus targets this issue. It aims to dissect the molecular mechanisms involved and identify key players in drug-induced side effects. As irAOPs are still in their infancy, there is a need for a model irAOP to validate the suitability of this tool. For this purpose, we developed a hepatotoxicity-based model irAOP for recombinant human IL-2 (aldesleukin). Besides producing durable therapeutic responses against renal cell carcinoma and metastatic melanoma, the boosted immune activation upon IL-2 treatment elicits liver damage. The availability of extensive data regarding IL-2 allows both the generation of a comprehensive putative irAOP and to validate the predictability of the irAOP with clinical data. Moreover, IL-2, as one of the first cancer immunotherapeutics on the market, is a blueprint for various biological and novel treatment regimens that are under investigation today. This review provides a guideline for further irAOP-directed research in immune-mediated hepatotoxicity. SN - 1547-6901 UR - https://www.unboundmedicine.com/prime/citation/38578203/IL-2-mediated_hepatotoxicity:_knowledge_gap_identification_based_on_the_irAOP_concept. DB - PRIME DP - Unbound Medicine ER -