Pharmacological Evaluation of TSLP Dependency in Preclinical Asthma Models 2246596

Abstract Introduction Asthma is a complex life-threatening disease. Deep phenotyping of preclinical models can reveal disease-driving mechanisms and guide new therapies. Methods Here, we benchmarked two well-established preclinical models of allergic airway inflammation, ovalbumin (OVA) and house dust mite (HDM), to define temporal dependence on thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine driving Th2 inflammation and is associated with clinical asthma severity. Our aim was to determine the time course of TSLP dependence in each model and assess whether prophylactic or therapeutic anti-TSLP treatment alters disease progression. Results We first confirmed that lung TSLP protein increased acutely after antigen challenge in both models. The OVA model produced bronchoalveolar lavage (BAL) eosinophil infiltration and elevated Th2 cytokines (TARC, IL-4, IL-5, and IL-13) across tissue compartments. Prophylactic administration of anti-mouse TSLP antibody (22E5) substantially mitigated OVA-induced airway inflammation. By contrast, 22E5 given after sensitization but before lung challenge failed to reduce eosinophilia or Th2 cytokines in either OVA or HDM models, despite HDM eliciting robust lung inflammation and lung TSLP upregulation. Conclusion These results defined a critical temporal window for TSLP dependence using a pharmacological approach in two of the most commonly used preclinical asthma models, shedding light on target validation and translational interpretation required for TSLP neutralization strategies. Funding Source N/A Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)