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  4. IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept
 
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2024
Journal Article
Title

IL-2-mediated hepatotoxicity: knowledge gap identification based on the irAOP concept

Abstract
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.
Author(s)
Roser, Luise
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Sakellariou, C.
Lindstedt, M.
Neuhaus, Vanessa  
Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM  
Dehmel, Susann  
Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM  
Sommer, Charline  
Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM  
Raasch, M.
Flandre, T.
Roesener, S.
Hewitt, P.
Parnham, Michael John  
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Sewald, Katherina  
Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM  
Schiffmann, S.
Journal
Journal of immunotoxicology  
Open Access
DOI
10.1080/1547691X.2024.2332177
Additional link
Full text
Language
English
Fraunhofer-Institut für Translationale Medizin und Pharmakologie ITMP  
Fraunhofer-Institut für Toxikologie und Experimentelle Medizin ITEM  
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