63 Pivotal Role of Intestinal Interleukin-17-Producing Gammadeltat Cells in the Food Allergy
The World Allergy Organization Journal
Atopic dermatitis (AD or eczema) often precedes the development of asthma and allergic rhinitis in atopic subjects, a phenomenon known as atopic march. An important role of epicutaneous (e.c.) sensitization has been recognized in the atopic march; however, the factors involved in e.c. sensitization remain poorly understood. Our previous studies using mouse models have shown that induced overexpression of Thymic Stromal Lymphopoietin (TSLP) in keratinocytes not only triggers an AD [Li, M. et al.
... n AD [Li, M. et al. Proc Natl Acad Sci U S A. 2006;103:11736-11741] but also aggravates experimental asthma induced by systemic sensitization and airway challenge of ovalbumin (OVA) [Zhang Z, et al. Proc Natl Acad Sci U S A. 2009;106:1536-1541, suggesting that TSLP represents an important factor linking AD to asthma. However, whether keratinocytic TSLP is essentially required for developing e.c. sensitization and triggering the atopic march remained to be determined. Methods: We develop a mouse model in which e.c. sensitization of OVA through tape-stripped skin is followed by intranasal challenge to induce an allergic asthma. TSLP ep2/2 mice (in which TSLP is selectively ablated in epidermal keratinocytes at adult stage) or TSLP over mice (in which keratinocytic TSLP overexpression is induced by topical application of MC903, a low-calcemic vitamin D analog) are subjected to this mouse model. Results: Upon OVA e.c. treatment, TSLP ep2/2 mice develop a defective allergen sensitization evidenced by decreased production of OVA-specific IgE and IgG1 and a reduction of the secretion of Th2 and Th17 (but not Th1) cytokines by in vitro OVA stimulated splenocytes. TSLP ep2/2 mice also exhibit a decreased OVA-induced skin inflammation. Finally, upon intranasal challenge, TSLP ep2/2 mice develop a less severe airway allergic inflammation and a reduced airway hyperresponsiveness. In contrast, overproduction of keratinocytic TSLP boosts the e.c. sensitization and triggers an aggravated asthma. Conclusions: Our results demonstrate an important role of keratinocytic TSLP in developing epicutaneous sensitization, generating allergic skin inflammation and triggering the atopic march. Thus, blocking the expression or activity of keratinocytic TSLP could be helpful to limit epicutaneous sensitization and prevent the atopic march. Background: Food allergy is a serious health problem, which affect 5% of children in westernized countries and evoke life-threatening hypersensitivity, termed anaphylaxis shock. Type 2 helper T cell (Th2) response and immunoglobulin E (IgE) has been implicated in the progression of food allergy, but the roles of specific lymphocyte subpopulations and cytokines remain to be clarified. Methods: The mucosal adjuvant, cholera toxin (CT) and ovalbumin (OVA) were co-administered orally into mice, while OVA alone could induce oral tolerance. To evaluate the contribution of various cytokines, we used interleukin-17 (IL-17) or IL-23 knockout (KO) and wild type (WT) mice as control. Results: Here we demonstrate that gamma delta T cells in the intestinal mucosa, as well as the cytokines interleukin-23 (IL-23) and IL-17, have pivotal roles to suppress the induction of serum OVA specific immunoglobulins and anaphylaxis in the food allergy model. The expression of IL-23, which was derived mostly from mucosal macrophages, and IL-17 levels were elevated after CT and OVA sensitization, and this induction of IL-17 was dependent on IL-23. Conclusions: These data, together with analysis of mice genetically disrupted for IL-17 and IL-23, suggest that IL-23 suppress the food allergy, whereas IL-17 has an important role in the anaphylaxis shock. Moreover, depletion of gamma delta T cells exacerbates the food allergy. We propose that T lymphocytes, including gamma delta T cells, could be a therapeutic target for mitigating the allergic response that evokes the anaphylaxis shock. Background: Neutrophils are often increased in the airways of either chronic severe disease or acute exacerbation of asthma. Neutrophils migrated in response to interleukin-8 (IL-8) may lead eosinophils to accumulate in the airways of asthma and possibly aggravate this disease. In this study, we investigated whether formoterol modify the trans-basement membrane migration (TBM) of eosinophils stimulated with neutrophils and IL-8. Methods: Neutrophils and eosinophils were isolated from peripheral blood obtained from healthy donors. The TBM of eosinophils was examined using a modified Boyden's chamber technique. Neutrophils were preincubated with or without formoterol (0.1 mM) at 378C for 30 minutes. Eosinophils were added to the upper compartment of a chamber with a Matrigel-coated transwell insert. Medium that contained preincubated neutrophils and IL-8 was added to the lower compartment of the chamber. After 90 minute incubation, migrated eosinophils in the lower chamber were calculated using eosinophil peroxidase assays. Results: A combination of neutrophils and IL-8 significantly induced TBM of eosinophils. Formoterol by itself did not modify the TBM of eosinophils. However, formoterol significantly attenuated TBM of eosinophils stimulated with neutrophils and IL-8. Conclusions: These results suggest that formoterol may act as a therapeutic agent on enhanced eosinophilic inflammation in acute exacerbation or persistent severe disease of asthma. This effect of formoterol likely involves inhibition of activation of neutrophils.