Neonatal IL-4 and IL-5 signaling drives long-term inflammation after early-life allergen exposure in a mouse model of allergic sensitization.

Background: Early-life exposure to allergens is a critical window that shapes immune development. Epidemiological and experimental evidence suggests that neonatal cytokine responses, particularly interleukin (IL)-4 and IL-5, drive type 2 immunity and increase the risk of allergic sensitization and asthma in adulthood. However, whether blocking these pathways in neonates can alter long-term susceptibility remains unclear. Methods: Neonatal BALB/c mice were exposed to 1% aerosolized ovalbumin (OVA) for 20 min, whereas controls received PBS. A subset of OVA-exposed neonates received 0.5 mg anti-IL-4 antibody at day 0. At adulthood (8 weeks), all groups were reexposed to aerosolized OVA. Blood and lung samples were collected for analysis of eosinophils, OVA-specific IgE, and cytokine production. Results: Mice exposed to aerosolized OVA as neonates exhibited elevated IL-4, IL-5, and IL-13, with increased eosinophilia and OVA-specific IgE, consistent with a type 2-biased response. PBS control neonatal mice challenged only in adulthood with aerosolized OVA showed no such sensitization. Strikingly, anti-IL-4 treatment at 2 days old prevented the dysregulated allergic sensitization and restored a balanced immune response, even upon OVA reexposure in adulthood. Anti-IL-4-treated neonates remained capable of mounting normal Th2 responses comparable with those observed in non-sensitized adult mice. Conclusion: Neonatal IL-4 and IL-5 signaling critically shapes long-term eosinophilic allergic sensitization. Early blockade of IL-4 prevents lifelong allergen-specific dysregulation, highlighting potential therapeutic benefits of cytokine-targeted interventions in infancy for the prevention of allergic diseases.