Asthma is a heterogeneous chronic inflammatory lung disease. Allergic asthma is characterized by airway hyperresponsiveness (AHR) 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 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. Notch signaling involves in cell fate decisions during development, cell proliferation and differentiation. Notch is a receptor that responds to cell surface-bound ligands. Notably, Notch ligand Jagged1 has immuno-suppressive properties and is considered especially good candidate for the role. Therefore, we constructed a Jagged1-expressing adenovirus vector (Ad-Jag1) and examined the activation and function of Ad-Jag1-transduced dendritic cells (Jag1-DCs) or mesenchymal stem cells (Jag1-MSCs). We predict that Jag1-DC (or Jag1-MSC) might induce protective immunity against Th2-mediated asthma by inducing Tregs. Actually, our preliminary results showed that Jag1-DCs promoted the development of Tregs in vitro. Jag1-DCs also expressed a therapeutic effect in an ovalbumin-induced asthmatic animal model. In addition, Jag1-MSCs markedly inhibited T-cell proliferation and blocked DCs activation in vitro. In this study, we aim to explore the anti-allergic ability of Jagged1 in the modification of immune cells activation, maturation, differentiation and function, and the in vivo immune-modulatory effects of Ad-Jag1 on cell-based treatment for the allergic asthma. The following hypotheses will be tested: Hypothesis 1: Jag1-DCs exert a distinctive phenotype and have the immunoregulatory ability to enhance the differentiation and functional capacity of Tregs.(1st year) Hypothesis 2: Jag1-MSCs possess the efficacious immunosuppressive capacity to induce the generation of Tregs and tolerogenic DCs, and inhibit mast cells activation.(2nd~3rd year) Hypothesis 3: Jag1-DCs (or Jag1-MSCs) may act as an immunomodulator to attenuate the severe syndromes of allergic asthma in mice.(2nd~3rd year) We want to alter the activation and functional behavior of bone marrow-derived DCs (or MSCs) through Ad-Jag1 transduction in vitro and subsequently observe what the effects of such modulation are on DCs and MSCs. Further, we evaluate whether Jag1-DCs (or Jag1-MSCs) treatment may suppress established Th2 response in ovalbumin-induced asthmatic mice. In summary, together with increased understanding of specific Jagged1-associated modulation of immune responses, this knowledge may ultimately result in DC- or MSC-based therapy to treat Th2-associated asthma. We deeply believe that our project may shed light on further understanding the regulatory mechanisms and designing more efficacious cell therapy for allergic diseases.
|Effective start/end date||8/1/17 → 7/31/18|