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Immune-related adverse outcome pathways (irAOPs) are a toxicological tool for the structuring of complex immunological mechanisms. The EU-funded IMI-project imSAVAR analyses the applicability of irAOPs in pre-clinical safety assessment of immunotherapies. Here, we use immunotherapy with interleukin (IL)-2 as a use case to develop an irAOP for IL-2-mediated vascular leakage (VL). Despite severe side effects observed upon high-dose treatment, IL-2 remains a promising candidate for cancer- and autoimmune therapy. The secondary systemic capillary leakage syndrome is described by a high mortality and a lethality rate of 20 - 30%. However, due to its non-specific symptoms, it remains a serious but under-diagnosed pathology. VL as general phenomenon is associated with several pro-inflammatory scenarios or observed as severe side effect of immunotherapies. In such situations, the physiological condition, in which endothelial cells (ECs) form the semipermeable seal of the vasculature, can escalate into pathological vascular permeability and finally VL. Although EC-biology and mechanisms underlying VL are ongoing subjects of research since many years, exact understanding of VL pathophysiology remains unclear. With this review, we provide an overview of the development of VL from an immunological perspective in the context of high-dose IL-2 immunotherapy. We structured the corresponding knowledge and generated an irAOP for IL-2-mediated VL with the aim to identify gaps and possible biomarkers. Gained insights from this theoretical approach facilitate the identification of relevant scientific questions as a basis for concrete experimental work. Integration of novel experiment-based knowledge into the existing irAOP could close a 'feedback-loop' by enabling irAOP-refinement and the identification of new questions. At the same time this could give rise to important information to improve test systems for IL-2-based immunotherapy safety-assessment and overall the approach to understand, prevent, or predict VL as critical side effect of other clinical conditions.