Therapeutic immunomodulation of allergic lung disease using regulatory dendritic cells in a mouse model of asthma
| dc.contributor.advisor | Gordon, John R. | en_US |
| dc.creator | Nayyar, Aarti | en_US |
| dc.date.accessioned | 2009-02-07T09:37:57Z | en_US |
| dc.date.accessioned | 2013-01-04T04:25:23Z | |
| dc.date.available | 2010-02-24T08:00:00Z | en_US |
| dc.date.available | 2013-01-04T04:25:23Z | |
| dc.date.created | 2009 | en_US |
| dc.date.issued | 2009 | en_US |
| dc.date.submitted | 2009 | en_US |
| dc.description.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. | en_US |
| dc.identifier.uri | http://hdl.handle.net/10388/etd-02072009-093757 | en_US |
| dc.language.iso | en_US | en_US |
| dc.subject | Immunomodulation | en_US |
| dc.subject | Th2 responses | en_US |
| dc.subject | Airway Hyperresponsiveness | en_US |
| dc.subject | Asthma | en_US |
| dc.subject | Dendritic cells | en_US |
| dc.subject | regulatory T cells | en_US |
| dc.subject | Interleukin-10 | en_US |
| dc.title | Therapeutic immunomodulation of allergic lung disease using regulatory dendritic cells in a mouse model of asthma | en_US |
| dc.type.genre | Thesis | en_US |
| dc.type.material | text | en_US |
| thesis.degree.department | Veterinary Microbiology | en_US |
| thesis.degree.discipline | Veterinary Microbiology | en_US |
| thesis.degree.grantor | University of Saskatchewan | en_US |
| thesis.degree.level | Doctoral | en_US |
| thesis.degree.name | Doctor of Philosophy (Ph.D.) | en_US |