The Role of TSLP in IL-13-Induced Atopic March

Although atopic dermatitis (AD) is the initial step of the “atopic march”, a progression from AD to asthma, the underlying mechanism remains unknown. Selective expression of IL-13 in the skin of mice caused an AD phenotype resembling human AD, and the disorder was associated with enhanced production of thymic stromal lymphopoietin (TSLP) in the AD skin with a systemic Th2 immunity. Here we show that IL-13 transgenic mice with AD had significantly enhanced lung inflammation, mucus hypersecretion, and airway hyperresponsiveness (AHR) when sensitized and challenged by allergen. In addition, the level of TSLP was significantly higher in acute AD than in chronic AD. Furthermore, elimination of TSLP signaling significantly diminished the allergic asthma responses, immune cell production of Th2 cytokines (IL-4, IL-13), and serum IgE. These studies indicate that IL-13 induces AD and atopic march via a TSLP dependent mechanism

Epicutaneous allergen application preferentially boosts specific T cell responses in sensitized patients

Abstract The effects of epicutaneous allergen administration on systemic immune responses in allergic and non-allergic individuals has not been investigated with defined allergen molecules. We studied the effects of epicutaneous administration of rBet v 1 and rBet v 1 fragments on systemic immune responses in allergic and non-allergic subjects. We conducted a clinical trial in which rBet v 1 and two hypoallergenic rBet v 1 fragments were applied epicutaneously by atopy patch testing (APT) to 15 birch pollen (bp) allergic patients suffering from atopic dermatitis, 5 bp-allergic patients suffering from rhinoconjunctivitis only, 5 patients with respiratory allergy without bp allergy and 5 non-allergic individuals. Epicutaneous administration of rBet v 1 and rBet v 1 fragments led to strong and significant increases of allergen-specific T cell proliferation (CLA+ and CCR4+T cell responses) only in bp-allergic patients with a positive APT reaction. There were no relevant changes of Bet v 1-specific IgE and IgG responses. No changes were noted in allergic subjects without bp allergy and in non-allergic subjects. Epicutaneous allergen application boosts specific T cell but not antibody responses mainly in allergic, APT-positive patients suggesting IgE-facilitated allergen presentation as mechanism for its effects on systemic allergen-specific immune responses

Thymic stromal lymphopoietin–elicited basophil responses promote eosinophilic esophagitis

Eosinophilic esophagitis (EoE) is a food allergy–associated inflammatory disease characterized by esophageal eosinophilia. Current management strategies for EoE are nonspecific, and thus there is a need to identify specific immunological pathways that could be targeted to treat this disease. EoE is associated with polymorphisms in the gene that encodes thymic stromal lymphopoietin (TSLP), a cytokine that promotes allergic inflammation, but how TSLP might contribute to EoE disease pathogenesis has been unclear. Here, we describe a new mouse model of EoE-like disease that developed independently of IgE, but was dependent on TSLP and basophils, as targeting TSLP or basophils during the sensitization phase limited disease. Notably, therapeutic TSLP neutralization or basophil depletion also ameliorated established EoE-like disease. In human subjects with EoE, we observed elevated TSLP expression and exaggerated basophil responses in esophageal biopsies, and a gain-of-function TSLP polymorphism was associated with increased basophil responses in patients with EoE. Together, these data suggest that the TSLP-basophil axis contributes to the pathogenesis of EoE and could be therapeutically targeted to treat this disease