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A1415 - Treatment with a CD200 Receptor Agonist Aptamer Attenuates Airway Hyperresponsiveness, Airway Inflammation, and Remodelling in a Chronic Murine Model of HDM-Induced Airways Inflammation
Author Block: L. Woo1, D. An1, W. Guo1, X. Wang1, A. Prodeus2, J. Gariépy2, J. A. Scott3, C. W. Chow4; 1Respirology, University Health Network, Toronto, ON, Canada, 2Molecular Targeting and Therapeutic Laboratory, Sunnybrook Research Insitute, Toronto, ON, Canada, 3University of Toronto, Toronto, ON, Canada, 4University Health Network Mars Centre, University of Toronto, Toronto, ON, Canada.
Background
CD200/CD200 receptor (CD200R) signalling initiates an anti-inflammatory signaling cascade that plays an important role in maintaining immune homeostasis. Dysregulation of the CD200/CD200R pathway has been reported in asthma. Our group had shown that a CD200R agonist aptamer dampens airway hyper-responsiveness (AHR) in an acute murine model of house dust mite (HDM) allergic airways inflammation. We hypothesized the agonist aptamer to be a therapy for asthma. We tested the hypothesis by administering the aptamer following the establishment of a chronic airways inflammation phenotype in a mouse model of HDM allergic airways inflammation. This chronic model differs from an acute model by the presence of airway remodelling, a key feature of asthma.
Methods
Female BALB/c mice (aged 8-12 weeks) were sensitized to intranasal HDM (25µg/35µl saline) Mon-Fri for 4 weeks followed by 2 days/week on weeks 5 and 6. Control mice received 35µl saline only. On weeks 5 and 6, mice were treated for 3 days/week with intranasal PEGylated agonist aptamer (30µg/35µl saline), PEGylated scrambled (control) aptamer (30µg/35µl saline) or 35µl saline only (sham) . Twenty-four hours after the last treatment, respiratory mechanics and methacholine-responsiveness was assessed using flexiVent®, followed by bronchoalveolar lavage (BALF), and harvesting of serum and lung tissue. A subgroup of lungs was inflation-fixed (25 cmH2O) for assessment of histolopathological indices of airways changes.
Results
HDM-exposed, sham-treated mice exhibited increased total (Rrs) and central (RN) airway resistance compared to Saline-exposed, sham-treated mice. HDM-exposed mice treated with the agonist aptamer demonstrated reduced Rrs and RN compared with the HDM, sham-treated mice. No significant changes in Rrs and RN were observed following treatment with the scrambled aptamer. The increases in BALF total leukocyte counts in HDM mice were not affected by any treatment. However, treatment with the agonist aptamer significantly reduced BALF eosinophils, and a trend for reduced neutrophils was also observed. Histological analysis of the lungs showed reduced peribronchial inflammatory infiltrates, goblet cell hyperplasia and collagen deposition in the agonist aptamer-treated HDM mice compared with sham-treated HDM mice.
Conclusion
Treatment with a CD200R agonist aptamer attenuated the three salient features of asthma (AHR, airway inflammation and airway remodelling) in a chronic model of HDM-induced allergic airways inflammation, suggesting that the aptamer has potential as a novel therapy for asthma.