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Food allergy in mice is modulated through the thymic stromal lymphopoietin pathway.

ABSTRACT: Thymic stromal lymphopoietin (TSLP) is involved in the pathogenesis of allergic reactions in the skin and the lung. Nevertheless, data on the role of TSLP in food allergy are scarce. We explored the role of TSLP in a mouse model with oral sensitization and oral challenge eliciting food allergy.TSLP receptor (TSLPR)-/- mice and wild type mice were orally sensitized to β-lactoglobulin in presence of cholera toxin (CT) or CT alone. The elicited immune response was characterized in vitro and the mice were subsequently challenged with the antigen. Lymphocytes from various locations in the gut were activated either by the antigen or by CT and assayed for cytokine secretion.Here we report that TSLPR-/- are less prone to generate food-induced reactions in conjunction with a decreased antigen-specific IgG1, but not IgE response. In addition, mesenteric lymphnode lymphocytes of TSLPR-/- mice were secreting lower quantities of IL-4, IL-5 and IL-10 after in vivo Ag activation, whereas higher numbers of IL-17 secreting cells were observed. Similarly, activation by the Th2-type adjuvant cholera toxin resulted in an increased frequency of IL-12 and IL-17 secreting lamina propria and mesenteric lymphocytes, together with increased production of IL-12 by activated dendritic cells in TSLPR-/- mice.TSLP can be considered as an essential, but not exclusive, mediator for elicitation of food allergy in mice, as well as a potential target for future therapeutic interventions.

SUBMITTER: Frossard CP

PROVIDER: S-EPMC4719751 | biostudies-other | 2015

REPOSITORIES: biostudies-other

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Project description:Thymic stromal lymphopoietin (TSLP) is a pleiotropic cytokine originally isolated from a murine thymic stromal cell line. TSLP exerts its biological effects by binding to a high-affinity heteromeric complex composed of thymic stromal lymphopoietin receptor chain and IL-7Rα. TSLP is primarily expressed by activated lung and intestinal epithelial cells, keratinocytes, and fibroblasts. However, dendritic cells (DCs), mast cells, and presumably other immune cells can also produce TSLP. Different groups of investigators have demonstrated the existence of two variants for TSLP in human tissues: the main isoform expressed in steady state is the short form (sf TSLP), which plays a homeostatic role, whereas the long form (lfTSLP) is upregulated in inflammatory conditions. In addition, there is evidence that in pathological conditions, TSLP can be cleaved by several endogenous proteases. Several cellular targets for TSLP have been identified, including immune (DCs, ILC2, T and B cells, NKT and Treg cells, eosinophils, neutrophils, basophils, monocytes, mast cells, and macrophages) and non-immune cells (platelets and sensory neurons). TSLP has been originally implicated in a variety of allergic diseases (e.g., atopic dermatitis, bronchial asthma, eosinophilic esophagitis). Emerging evidence indicates that TSLP is also involved in chronic inflammatory (i.e., chronic obstructive pulmonary disease and celiac disease) and autoimmune (e.g., psoriasis, rheumatoid arthritis) disorders and several cancers. These emerging observations greatly widen the role of TSLP in different human diseases. Most of these studies have not used tools to analyze the expression of the two TSLP isoforms. The broad pathophysiologic profile of TSLP has motivated therapeutic targeting of this cytokine. Tezepelumab is a first-in-class human monoclonal antibody (1) that binds to TSLP inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety and efficacy. Several clinical trials are evaluating the safety and the efficacy of tezepelumab in different inflammatory disorders. Monoclonal antibodies used to neutralize TSLP should not interact or hamper the homeostatic effects of sf TSLP.

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Food allergy in mice is modulated through the thymic stromal lymphopoietin pathway.

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