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      Therapeutic immunomodulation of allergic lung disease using regulatory dendritic cells in a mouse model of asthma

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      Date
      2009
      Author
      Nayyar, Aarti
      Type
      Thesis
      Degree Level
      Doctoral
      Metadata
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      Abstract
      We report herein that IL-10-treated dendritic cells (DC) can be used effectively to reverse established severe asthma-like disease in a mouse model. Our lab had shown previously that allergen-presenting splenic CD8α⁺ DCs could ≈50% reduce airway hyper responsiveness (AHR), eosinophilia, and Th2 responses in asthma-phenotype mice, but only marginally reduce IgE/IgG1 levels. We now show that bone marrow-derived DCs that have been differentiated in the presence of IL-10 (DCIL-10) are effective in reversing the asthma phenotype. Co-culture of DCIL-10 with T memory (TM) cells from asthma-phenotype mice was associated with lack of Th2 responses, and this was partially reversed by IL-2. Immunostimulatory DC activated these Th2 cells. In vivo, delivery of allergen-pulsed DCIL-10, either into the airway or intraperitoneally abrogated AHR from weeks 3-10 post-treatment, and ameliorated lung eosinophilia and Th2 (IL-4, -5, -9, & -13, IgE) responses, as well as circulating allergen-specific IgE responses for at least 32 weeks following treatment. Repeated OVADCIL-10 treatments kept AHR normalized for 8 weeks as well as Th2 responses significantly low. In vivo, delivery of anti-IL-10R, but not anti-TGF-β from day 12-21 after treatment had moderate effects on DCIL-10-driven tolerance, but 1-methyl tryptophan (inhibitor of indoleamine-2,3-dioxygenase) treatment had significant effects on Th2 responses. The mechanisms mediating tolerance in vivo are likely complex, but we speculate that infectious tolerance sustains this regulatory activity during the 32-week period in which we have observed tolerance to be in place.
      Degree
      Doctor of Philosophy (Ph.D.)
      Department
      Veterinary Microbiology
      Program
      Veterinary Microbiology
      Supervisor
      Gordon, John R.
      Copyright Date
      2009
      URI
      http://hdl.handle.net/10388/etd-02072009-093757
      Subject
      Immunomodulation
      Th2 responses
      Airway Hyperresponsiveness
      Asthma
      Dendritic cells
      regulatory T cells
      Interleukin-10
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