ABSTRACT Allergen immunotherapy (AIT) is currently the only disease‐modifying therapy for allergic airway inflammation. However, its underlying mechanisms remain incompletely understood, which in turn impede the development of more effective and durable treatment strategies. Although animal models are indispensable for mechanistic dissection and therapeutic innovation, they are limited by significant translational gaps arising from fundamental interspecies immunological differences, variability in modeling protocols, and the frequent conflation of short‐term desensitization with durable clinical tolerance. This review critically evaluates current animal models of AIT, particularly murine models, by systematically comparing their immunological parameters and treatment paradigms with human clinical pathophysiology. We analyze the effects of animal strain, allergen type, intervention timing, and administration route on the observed mechanisms of tolerance. Furthermore, we assess the utility of these models in optimizing next‐generation strategies, including adjuvants and combination biologics. We conclude by proposing a conceptual framework to enhance translational relevance, emphasizing the need for standardized and clinically aligned protocols, integration of chronic and humanized models, and the synergistic use of emerging technologies such as organoids and artificial intelligence. This framework aims to guide the development of predictive preclinical models that can accelerate the rational design of novel AIT therapies.
Zhang et al. (Mon,) studied this question.