Allergic asthma is characterized by airway hyperresponsiveness to specific and non-specific stimuli with elevated serum IgE levels and eosinophilic inflammation. It is well known that allergen-specific CD4 + type 2, T-helper (Th2) cells and immunoglobulin E (IgE)-sensitized mast cells are key players in the allergic response. Therefore, therapeutic strategies that induce regulatory T cells (Tregs) to suppress Th2-cell responses and inhibit IgE-mediated activation on mast cells seem to have the greatest potential to efficiently inhibit allergen-induced disorders. Short-chain fatty acids (SCFAs) have anti-inflammatory and immuno-suppressive properties and are considered especially good candidates for the role. Actually, our preliminary results showed that SCFA-phenylbutyrate (PB) induced tolerogenic dendritic cells, enhanced the generation of splenic Foxp3 + Tregs and inhibited mast cell degranulation. PB also expressed a preventive effect in an ovalbumin-induced asthmatic animal model. Therefore, we aim to explore the anti-allergic ability and regulatory mechanisms of PB and other SCFAs in the modulation of immune cells activation, maturation differentiation and function, and the in vivo immune-modulatory effects of SCFAs in the allergic diseases, such as allergic asthma and atopic dermatitis. The following hypotheses will be tested: Hypothesis 1: SCFAs act as an immune-modulatory agent to induce tolerogenic dendritic cells through modulation of HIF-1α/NF-B signaling pathway. Hypothesis 2: SCFAs act as an immune-modulator agent to enhance the differentiation and functional capacity of regulatory T cells. Hypothesis 3: SCFAs act as an immunosuppressive agent to inhibit the activation of mast cells through modulation of JNK/NFκB signaling pathway. Hypothesis 4: SCFAs may act as an immune-modulator to attenuate the severe syndromes of allergic asthma and atopic dermatitis in mouse models. We want to alter the functional behavior of bone-marrow derived DCs through a selection of SCFAs modification in vitro and subsequently observe what the effects and regulatory mechanisms of such modulation are on DCs. We also want to clarify how SCFAs induce Tregs from naïve CD4 + T cells and how these Tregs mediate their suppression. Besides, the effects of SCFAs on IgE-mediated allergic responses in RBL-2H3 cells are investigated. Finally, we evaluate whether SCFAs treatment may suppress established Th2 response by inducing Tregs or inhibiting the activation of mast cells in animal models. In summary, together with increased understanding of specific SCFAs-associated modulation of immune responses, this knowledge may ultimately result in SCFAs-based therapy to treat atopic asthma. We deeply believe that our project may shed light on further understanding the regulatory mechanisms and designing more efficacious immunotherapy for allergic diseases.
|Effective start/end date||8/1/14 → 7/31/15|
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