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The Genetic Control of Airway Responsiveness and the Effect of Resiquimod Treatment on Allergic Asthma

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The Genetic Control of Airway Responsiveness and the Effect of Resiquimod Treatment on Allergic Asthma The genetic control of airway responsiveness and the effect of resiquimod treatment on allergic asthma By: Pierre Camateros Department of Medicine, Division of Experimental Medicine McGill University, Montreal A thesis submitted to McGill University in partial fulfilment of the requirements of the degree of Doctor of Philosophy ©Pierre Camateros 2009 Library and Archives Bibliothèque et Canada Archives Canada Published Heritage Direction du Branch Patrimoine de l’édition 395 Wellington Street 395, rue Wellington Ottawa ON K1A 0N4 Ottawa ON K1A 0N4 Canada Canada Your file Votre référence ISBN: 978-0-494-68509-9 Our file Notre référence ISBN: 978-0-494-68509-9 NOTICE: AVIS: The author has granted a non- L’auteur a accordé une licence non exclusive exclusive license allowing Library and permettant à la Bibliothèque et Archives Archives Canada to reproduce, Canada de reproduire, publier, archiver, publish, archive, preserve, conserve, sauvegarder, conserver, transmettre au public communicate to the public by par télécommunication ou par l’Internet, prêter, telecommunication or on the Internet, distribuer et vendre des thèses partout dans le loan, distribute and sell theses monde, à des fins commerciales ou autres, sur worldwide, for commercial or non- support microforme, papier, électronique et/ou commercial purposes, in microform, autres formats. paper, electronic and/or any other formats. The author retains copyright L’auteur conserve la propriété du droit d’auteur ownership and moral rights in this et des droits moraux qui protège cette thèse. Ni thesis. Neither the thesis nor la thèse ni des extraits substantiels de celle-ci substantial extracts from it may be ne doivent être imprimés ou autrement printed or otherwise reproduced reproduits sans son autorisation. without the author’s permission. In compliance with the Canadian Conformément à la loi canadienne sur la Privacy Act some supporting forms protection de la vie privée, quelques may have been removed from this formulaires secondaires ont été enlevés de thesis. cette thèse. While these forms may be included Bien que ces formulaires aient inclus dans in the document page count, their la pagination, il n’y aura aucun contenu removal does not represent any loss manquant. of content from the thesis. LIST OF ABBREVIATIONS ..................................................................................... 4 PREFACE AND CONTRIBUTION OF AUTHORS ...................................................... 7 ABSTRACT ........................................................................................................... 9 RÉSUMÉ ............................................................................................................ 11 GENERAL INTRODUCTION ................................................................................. 14 CHAPTER 1 - LITERATURE REVIEW..................................................................... 18 Abstract ...............................................................................................................................19 1. Epidemiology and Pathogenesis of Asthma ......................................................................20 2. Role of Toll-Like Receptors (TLR) Signalling in the Pathogenesis of Asthma .....................27 3. Future Directions .............................................................................................................35 Acknowledgements .............................................................................................................39 Figure 1: TLR, the Immune System, and Asthma ..................................................................41 CHAPTER 2 - TLR7 LIGAND PREVENTS ALLERGEN-INDUCED AIRWAY HYPERRESPONSIVENESS AND EOSINOPHILIA IN ALLERGIC ASTHMA BY A MYD88-DEPENDENT AND MAPKAPK2-INDEPENDENT PATHWAY ..................... 43 Preface.................................................................................................................................44 Abstract ...............................................................................................................................45 Introduction .........................................................................................................................46 Material and Methods .........................................................................................................48 Results .................................................................................................................................51 Discussion ............................................................................................................................56 Acknowledgements .............................................................................................................60 Table 1: Primer sequences for real time quantitative PCR....................................................61 Figure 1: Treatment with Resiquimod Abrogates Allergen Induced AHR. ............................62 Figure 2: IgE Levels in OVA Challenged A/J and C57BL/6 mice..............................................64 Figure 3: Cytokine Levels Following OVA Challenge. ............................................................66 Figure 4: Chemokine mRNA Expression Following OVA Challenge. ......................................68 Figure 5: BAL Analysis. .........................................................................................................70 Figure 6: Histological Analysis of Lungs from OVA Challenged mice. ....................................72 Figure 7: Lung Eosinophilia Following OVA Challenge is Inhibited by Resiquimod. ...............74 CHAPTER 3 - CHRONIC ASTHMA-INDUCED AIRWAY REMODELING IS PREVENTED BY TOLL-LIKE RECEPTOR-7/8 LIGAND RESIQUIMOD.......................................... 76 Preface.................................................................................................................................77 Abstract ...............................................................................................................................78 Introduction .........................................................................................................................79 1 Materials and Methods........................................................................................................82 Results .................................................................................................................................87 Discussion ............................................................................................................................94 Acknowledgements .............................................................................................................98 Table 1: Lung Cytokine Levels 24 and 48 Hours Post Challenge ............................................99 Figure 1: Inflammatory Cells in the BALF ........................................................................... 100 Figure 2: Inflammation in Lung Tissues ............................................................................. 102 Figure 3: Plasma IgE Levels. ................................................................................................ 104 Figure 4: Cytokine Levels Following Acute Antigen Challenge ............................................ 106 Figure 5: Inflammation in the Lungs of Chronically Challenged Rats ................................. 108 Figure 6: Smooth Muscle Mass of Chronically Challenged Rats .......................................... 110 Figure 7: Goblet Cell Hyperplasia in Chronically Challenged Rats ....................................... 112 Figure 8: Proliferation of Airway Cell in Response to Chronic Challenge ............................ 114 CHAPTER 4 - MODULATION OF THE ALLERGIC ASTHMA TRANSCRIPTOME FOLLOWING RESIQUIMOD TREATMENT ......................................................... 116 Preface............................................................................................................................... 117 Abstract: ............................................................................................................................ 118 Introduction ....................................................................................................................... 119 Materials and Methods...................................................................................................... 122 Results ............................................................................................................................... 127 Discussion .......................................................................................................................... 138 Acknowledgements ........................................................................................................... 148 Table 1: Pathways Different Between A/J and C57BL/6 Mice............................................. 149 Table 2: Genes Altered After Antigen Challenge in A/J Mice Only ...................................... 150 Table 3: Top 30 Genes Altered by Antigen Challenge .................................................. 151 Table 4: Pathways Altered by Antigen Challenge or Resiquimod Treatment ...................... 153 Table 5: Top 30 Genes Altered by Resiquimod Treatment.................................................. 154 Table 6: Significantly Altered Genes Following Antigen Exposure in Different Studies ....... 156 Figure 1: Summary of the Total Numbers of Differentially Expressed
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