IL2-induced hepatotoxicity map

Online access and exploration: https://imsavar.elixir-luxembourg.org
Development status: Available for exploration online
Diseases treated: Cancer, autoimmune diseases
Sustainable support: LCSB, MINERVA Platform
Construction tool: CellDesigner
Funding: IMI2 imSAVAR No 853988, https://imsavar.eu
License: Creative Commons Attribution 4.0 International (CC BY 4.0) License
Publication: Manuscript in preparation
Contact: Oxana Lopata, University of Luxembourg, oxana.lopata(at)uni.lu

Description

The IL2-induced hepatotoxicity map is accessible here. It is developed to identify and represent IL2 related cytotoxic mechanisms in the liver, and to analyse data on two variants of the IL2 immunotherapy - Aldesleukin and MHS554. The content of the map is discussed and validated in consultations with ImSAVAR experts. The map is organised into three biological response levels - molecular, cellular, and organ, and comprises four key events: IL2 binding to cells, activation of cytokine or receptor expression, recruitment and adhesion to liver sinusoids, and hepatocyte damage.

The map is structured into two layers. First is the main map which depicts tissue compartments, cell types, and molecular entities, including cytokines, chemokines, small molecules, and their corresponding receptors, with the interactions between them. This layer focuses on intercellular communication and the connectivity of molecular activities across the liver microenvironment. The second layer includes submaps for key cell types, such as hepatocytes and CD8+ T cells. They show intracellular mechanisms and provide detailed views of cell specific mechanisms relevant to IL2 induced hepatotoxicity.

Omics visualisation

Data overlays derived from differentially expressed genes (DEGs) in the ImSAVAR dataset were generated and integrated into the IL2 hepatotoxicity map. They visualise affected molecules and interactions in the map to inform about most relevant pathways and cell types concerning lL2 induced hepatotoxicity mechanisms. Their comparative analysis indicates that Aldesleukin activates multiple cytotoxic mediators and their corresponding hepatocyte receptors, leading to apoptosis-related pathways activation. However MHS554 did not trigger comparable activation of these key cytotoxic mechanisms. This analysis supports a reduced hepatotoxic liability for MHS554 and highlights mechanistic differences between the two IL2 based therapies.

Modelling

Text

Image4

Funding

This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking under grant agreement No 853988.

Acknowledgements

This project is supported by ELIXIR Luxembourg (ELIXIR-LU) Node. ELIXIR-LU hosts and maintains the MINERVA Platform for this project and supports its development.