Machine-readable immune ontogeny maps for AOP-anchoring: A critical review

The adverse outcome pathway framework has become a central organizing structure in regulatory and predictive toxicology, and a well-resourced international effort is now underway to build a machine-readable map of human immune system development for exactly this purpose. This review critically examines that emerging effort and the surrounding technical landscape, asking what a machine-readable immune ontogeny map needs to contain, how it should be represented, and how far current and proposed resources actually get toward supporting adverse outcome pathway key events as computable, age-indexed biological states. We describe the Human Immune System Development Map, a systems-biology network representation built on disease-map conventions, situate it within the wider Partnership for the Assessment of Risks from Chemicals developmental immunotoxicity initiative, and compare its representational choices against an alternative built on standardized biomedical ontologies for cell type, anatomy, and developmental stage. We survey human and zebrafish immune ontogeny atlases, the ontology infrastructure available for cross-species annotation, and emerging large language model-based tools for adverse outcome pathway curation, and we identify specific respects in which the existing map is human-only, based on a graphical systems-biology representation rather than formally ontology-tagged, and not yet interoperable with the semantic web representation of the adverse outcome pathway wiki. We propose a complementary, ontology-tagged and cross-species extension architecture designed to interoperate with, rather than duplicate, the existing systems-biology map, and we identify the curation, versioning, and validation obstacles that stand between current resources and routine regulatory use. The review concludes that the foundational infrastructure for this integration is being actively built, but that closing the gap between systems-biology network maps and formally ontology-anchored, cross-species adverse outcome pathway key events remains substantially unfinished work.