Asthma is a heterogeneous chronic inflammatory lung disease. Allergic asthma is characterized by airway hyperresponsiveness to specific and non-specific stimuli with elevated serum immunoglobulin E (IgE) levels and airway inflammation. It is well known that allergen-specific CD4+ type 2, T-helper (Th2) cells, dendritic cells (DCs), and IgE-sensitized mast cells are key players in the Th2-mediated allergic asthma. 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. Catalpol, an iridiod glucoside isolated from the root of Rehmannia glutinosa, has received considerable attention because it has a variety of biological and pharmacological properties including anti-inflammatory and immunomodulatory effects. Thus, we propose that the bioactivities of catalpol may potentially be able to influence immune cell functions and provide a new alternative option for relieving symptoms of allergic diseases. Actually, our preliminary results showed that catalpol promoted the development of Tregs in vitro. Catalpol also expressed a therapeutic effect in an ovalbumin (OVA)-induced asthmatic animal model. Therefore, we want to explore the anti-allergic ability and regulatory mechanisms of catalpol in the modulation of immune cells activation, maturation, differentiation and function, and the in vivo immune-modulatory effects of catalpol in the allergic diseases, such as allergic asthma and atopic dermatitis. The following hypotheses will be tested:Hypothesis 1: Catalpol-treated DCs exert a distinctive phenotype and have the immune-regulatory ability to promote Treg responses. (1st year)Hypothesis 2: Catalpol directly suppresses T cell activation and drives the differentiation of CD4+ T cells into Tregs. (2nd year)Hypothesis 3: Catalpol reduces the activation of IgE/OVA-stimulated mast cells through modulation of MAP kinases /NF-κB signaling pathways. (2nd year)Hypothesis 4: Catalpol may act as an immunomodulator to attenuate the severe syndromes of allergic asthma and atopic dermatitis in mice. (3rd year) We want to alter the functional behavior of bone marrow-derived DCs through catalpol modification and subsequently observe what the effects of such modulation are on DCs. We also want to clarify whether catalpol directly induces Tregs from CD4+ T cells. Besides, the effects of catalpol on IgE-mediated allergic responses in bone marrow-derived mast cells are investigated. Finally, we evaluate whether catalpol 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 catalpol-associated modulation of immune responses, this knowledge may ultimately result in catalpol-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||8/1/18 → 7/31/19|
- allergic asthma
- dendritic cell
- mast cell
- Th2 cell
- regulatory T cell
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