Roser, LuiseLuiseRoserSakellariou, C.C.SakellariouLindstedt, M.M.LindstedtNeuhaus, VanessaVanessaNeuhausDehmel, SusannSusannDehmelSommer, CharlineCharlineSommerRaasch, M.M.RaaschFlandre, T.T.FlandreRoesener, S.S.RoesenerHewitt, P.P.HewittParnham, Michael JohnMichael JohnParnhamSewald, KatherinaKatherinaSewaldSchiffmann, S.S.Schiffmann2024-07-092024-07-092024https://publica.fraunhofer.de/handle/publica/47118810.1080/1547691X.2024.23321772-s2.0-8518945063238578203Drug-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.enopen accessjournal article