Targeting IL-33 and TSLP in Asthma: Efficacy Assessment in Humanized Mouse Models 2302202

Abstract Introduction Interleukin-33 (IL-33) and thymic stromal lymphopoietin (TSLP) are key epithelial cytokines driving allergic inflammation and asthma. IL-33/ST2 signaling activates type 2 immune responses, while TSLP functions as an upstream initiator of multiple inflammatory pathways. Both cytokines are promising therapeutic targets, with several IL-33— and TSLP-directed antibodies in development. Methods To enable in vivo evaluation of human-specific drug candidates, two humanized mouse models were generated: B-hIL33/hTSLP/hTSLPR, in which human IL33, TSLP, and TSLPR replace their murine genes, and B-hIL33(C), expressing only human IL-33. An ovalbumin (OVA)—induced asthma model was established in both backgrounds. Mice received anti-human IL-33 antibody monotherapy or combination therapy with anti-human TSLP. Endpoints included eosinophil counts, serum IgE, and lung histopathology (H&E). Results Both models were successfully validated, producing only human IL-33, TSLP, and TSLPR with complete loss of murine protein expression. In OVA-challenged mice, anti-IL-33 treatment significantly decreased eosinophil infiltration and IgE levels, with lung sections showing reduced inflammatory cell accumulation and mucus secretion. Importantly, in the triple-humanized B-hIL33/hTSLP/hTSLPR mice, dual blockade of IL-33 and TSLP produced greater suppression of airway inflammation compared with monotherapy, demonstrating additive therapeutic benefit. Conclusion The B-hIL33/hTSLP/hTSLPR and B-hIL33(C) humanized mouse models provide robust platforms for evaluating IL-33— and TSLP-targeted therapies. Their validated human cytokine signaling enables meaningful preclinical assessment of monoclonal or combination strategies, supporting advancement of next-generation biologics for allergic and inflammatory diseases. Funding Source N/A Topic Categories Immediate Hypersensitivity, Asthma, and Allergic Responses (HYP)