The genetic control of airway responsiveness and the effect of resiquimod treatment on allergic asthma

Asthma is a heterogeneous airway disease caused by a mixture of genetic and environmental factors which result in improper immune responses to innocuous antigens. Toll-like receptors (TLR) are pathogen associated pattern recognition receptors which form homo- or heterodimers which bind specific ligands leading to activation and modulation of immune responses. The present study examined the effect of resiquimod, a synthetic toll-like receptor 7 ligand, on the development of allergic asthma pathology in animal models. Resiquimod treatment of ovalbumin sensitized mice prevented the subsequent development of airway hyperresponsiveness and inflammation, increased plasma IgE levels, and both TH1 and TH2 cytokine production. This effect was independent of the Mapkapk2 gene but was ineffective in Myd88 knockout mice.;Employing gene expression microarray analysis, the transcriptome of resiquimod treated, and untreated asthmatic A/J and C57BL/6 mice, was characterized. Asthma induction resulted in the up-regulation of genes involved with the control of cell cycle progression, the complement and coagulation cascades, and chemokine signalling, findings which are consistent with previous reports. Treatment with resiquimod resulted in the normalization of asthma induced genes related to airway remodelling and chemokine signalling. Additionally, treatment resulted in the induction of cell adhesion genes, and genes involved in natural killer (NK) cell-mediated cytotoxicity. Furthermore, NK cell recruitment to the lungs and livers of resiquimod treated mice was demonstrated, though treatment efficacy was not dependent on these cells.;The difference in asthma susceptibility between A/J and C57BL/6 mice was further explored at the genetic level. Specifically, airway responsiveness, a predisposing factor for the development of asthma in humans, was assessed using a panel of 33 recombinant congenic strains of mice derived from A/J and C57BL/6 parental strains. A genotype-phenotype association analysis was then performed and identified 16 chromosomal regions as significantly associated with airway responsiveness. Of these 16 regions, 8 are novel while the remainder have previously been linked with airway responsiveness. Several likely candidates have been identified from these 16 regions, but further study will be required in order to determine if these genes have any causal relationship with airway responsiveness.;Overall, the data presented in this thesis demonstrate and characterize the protective effect of resiquimod treatment against both the acute and chronic pathological changes associated with the development of asthma. Furthermore, genetic factors which are associated with a predisposition to the development of asthma and with asthma pathology have been described at the genetic and transcriptional levels, respectively. Taken together, these findings further our understanding of the molecular basis of asthma pathology and will aid in the development of new therapeutic strategies.;A defining feature of asthmatic airways is airway wall remodelling which is characterized by an increase in airway smooth muscle mass, goblet cell hyperplasia, and the deposition of extra-cellular matrix components. The effects of resiquimod treatment on the development of airway remodelling were examined in Brown Norway rats. Resiquimod treatment prevented the increase in airway smooth muscle mass and goblet cell hyperplasia observed in control animals. These effects were associated with a reduction in the number of proliferating airway cells and were preceded by an abrogation of the allergic inflammatory reaction.