HIDmap: a physiology-based map of human immune system development to support animal-free research and regulatory...

Human immune system development is established through a sequence of tightly regulated processes occurring across multiple embryonic and fetal organs. Despite extensive research, our mechanistic understanding still relies largely on animal models, which often lack translational precision for human biology. This gap is particularly relevant for developmental immunotoxicity (DIT), where early-life exposure to environmental contaminants such as dioxins, PCBs, and PFAS has been associated with long-term immune dysfunction, including reduced vaccine responsiveness in children. To address this need, we created the Human Immune System Development Map (HIDmap), a curated, findability, accessibility, interoperability, and reusability (FAIR)-compliant digital resource that systematically captures prenatal immune ontogeny. The HIDmap integrates literature-derived data into a modular, three-layered structure linking anatomical niches, cell migration, and differentiation trajectories across 24 organs. Implemented in the MINERVA (Molecular Interaction NEtwoRks VisuAlization) platform, the HIDmap allows interactive exploration of developmental processes and molecular markers relevant to immune function. By embedding the HIDmap within the Adverse Outcome Pathway (AOP) framework, we constructed a putative AOP to demonstrate how the map can help to connect molecular initiating events related to environmental exposures - such as Aryl hydrocarbon receptor (AhR) activation - to downstream immunological key events and adverse outcomes. This resource offers a human-centered foundation for curating and visualizing human developmental immunobiology and may support the future development of predictive in vitro New Approach Methodologies (NAMs). In the future, the HIDmap may contribute to the identification of critical windows of susceptibility and support the advancement of mechanism-based, animal-free approaches in developmental immunotoxicology.