[en] This work focuses on the need for modeling and predicting adverse outcomes in immunotoxicology to improve nonclinical assessments of the safety of immunomodulatory therapies. The integrated approach includes, first, the adverse outcome pathway concept established in the toxicology field, and, second, the systems medicine disease map approach for describing molecular mechanisms involved in a particular pathology. The proposed systems immunotoxicology workflow is illustrated with chimeric antigen receptor (CAR) T cell treatment as a use case. To this end, the linear adverse outcome pathway (AOP) is expanded into a molecular interaction model in standard systems biology formats. Then it is shown how knowledge related to immunotoxic events can be integrated, encoded, managed, and explored to benefit the research community. The map is accessible online at https://imsavar.elixir-luxembourg.org via the MINERVA Platform for browsing, commenting, and data visualization. Our work transforms a graphical illustration of an AOP into a digitally structured and standardized form, featuring precise and controlled vocabulary and supporting reproducible computational analyses. Because of annotations to source literature and databases, the map can be further expanded to match the evolving knowledge and research questions. [en] In immunotoxicology, an adverse outcome pathway shows a sequence of molecular and cellular events that result in a toxic outcome upon treatment with a specific drug.In systems biomedicine, a disease map is a description of disease mechanisms on the levels of molecular interactions and intercellular communication for integrating prior knowledge, making sense of newly-generated data, modeling and predictions.We are applying the disease map approach to the area of immunotoxicology and offer an interactive web-based platform for expanding immune-related adverse outcome pathways to detailed representations of the underlying biology.The objective is to model adverse outcomes as a nonclinical assessment strategy by integrating our understanding of the disease complexity and knowledge on the mechanisms of the adverse outcomes of the treatment.We focus on the adverse outcome pathway of CAR T cell treatment and from a simplified linear pathway build a detailed representation of the underlying biology.
Disciplines :
Human health sciences: Multidisciplinary, general & others
Alb, Miriam ; Universitätsklinikum Würzburg, Medizinische Klinik und Poliklinik II, Lehrstuhl für Zelluläre Immuntherapie, Würzburg, Germany
Sakellariou, Christina ; Department of Immunotechnology, Lund University, Lund, Sweden
Sommer, Charline ; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Preclinical Pharmacology and In-Vitro Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Sewald, Katherina ; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Preclinical Pharmacology and In-Vitro Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Reiche, Kristin ; Department of Diagnostics, Fraunhofer Institute for Cell Therapy and Immunology IZI, Leipzig, Germany
Gogesch, Patricia ; Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany
Roser, Luise A ; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
Ortega Iannazzo, Samira ; Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany
Schiffmann, Susanne ; Fraunhofer Institute for Translational Medicine and Pharmacology ITMP, Frankfurt am Main, Germany
Waibler, Zoe ; Division of Immunology, Paul-Ehrlich-Institut, Langen, Germany
Neuhaus, Vanessa ; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Preclinical Pharmacology and In-Vitro Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
Dehmel, Susann ; Fraunhofer Institute for Toxicology and Experimental Medicine ITEM, Preclinical Pharmacology and In-Vitro Toxicology, Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Member of the Fraunhofer Cluster of Excellence Immune-Mediated Diseases CIMD, Hannover, Germany
SATAGOPAM, Venkata ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Clinical and Translational Informatics ; ELIXIR Luxembourg, Belvaux, Luxembourg
SCHNEIDER, Reinhard ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Bioinformatics Core ; ELIXIR Luxembourg, Belvaux, Luxembourg
OSTASZEWSKI, Marek ; University of Luxembourg ; ELIXIR Luxembourg, Belvaux, Luxembourg
GU, Wei ; University of Luxembourg ; ELIXIR Luxembourg, Belvaux, Luxembourg
This work was part of the imSAVAR project and was supported by the imSAVAR Consortium ( https://imsavar.eu/consortium ). We would like to acknowledge the Responsible and Reproducible Research (R3) team of the Luxembourg Centre for Systems Biomedicine for supporting the project. The work presented in this paper was carried out using the ELIXIR Luxembourg tools and services. The Paul-Ehrlich-Institut receives funding exclusively from the EU Commission.This project has received funding from the Innovative Medicines Initiative (IMI) 2 Joint Undertaking (JU) under grant agreement No [853988]. The JU receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA and JDRF INTERNATIONAL. This work was part of the imSAVAR project and was supported by the imSAVAR Consortium (https://imsavar.eu/consortium). We would like to acknowledge the Responsible and Reproducible Research (R3) team of the Luxembourg Centre for Systems Biomedicine for supporting the project. The work presented in this paper was carried out using the ELIXIR Luxembourg tools and services. The Paul-Ehrlich-Institut receives funding exclusively from the EU Commission.
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