Cytotoxic T cell-mediated immunotherapy of allergic airway inflammation
The worldwide incidence of atopic disease, including asthma, has increased dramatically over the last few decades. In New Zealand, asthma affects at least one in four children and one in six adults, a prevalence among the highest reported in the world. Up to half of these individuals suffer from exacerbations of disease that are driven by allergic airway inflammation. Key instigators of allergic airway inflammation are CD4+ Th2 cells that respond to normally harmless inhaled antigens presented by airway-surveying antigen presenting cells (APC). Th2 production of chemical mediators subsequently induces eosinophilia, mucus hypersecretion and airway remodeling; the characteristic features of allergic airway pathology. Allergen-specific cytotoxic T lymphocytes (CTL) can ameliorate airway inflammation in a model of acute allergic airway inflammation, however, the mechanism of their inhibitory activity is not fully defined. Furthermore, the effects of CTLs on established airway inflammation, like that which presents clinically, have not been elucidated. In this thesis, a mouse model of allergic airway inflammation was established and characterised, where multiple allergen exposures stimulated significant airway pathology. Additionally, a model involving the adoptive transfer of in vitro-generated Th2 cells into naive hosts was developed to investigate the cellular interactions, phenotype, and disease-mediating functions of these cells during active inflammation. Pathology was examined by enumeration of lung- and airway-infiltrating inflammatory cells, assessment of the extent of mucus production, as well as the measurement of inflammatory mediators. Lung tissue was also examined microscopically to investigate the interaction of CTLs with key disease-mediating cells: Th2 cells and APCs – specifically, lung CD103+ and CD11b+ dendritic cells (DCs). The cellular targets of cytolytic CTLs were additionally investigated by use of fluorescent probes to detect the expression of active cell-apoptosis-associated caspases within dying cells. Treatment with allergen-specific CTLs was found to suppress inflammation over multiple allergen challenges, and was additionally effective in the amelioration of established allergic airway inflammation. Therapeutic success was associated with reduced early cytokine production by Th2 cells in lung, as well as diminishing their subsequent accumulation and production of IL-4 and IL-13. In addition, treatment with CTLs increased the proportion of caspase+ DCs in the lung-draining mediastinal lymph node and decreased the numbers of CD103+ and CD11b+ DC in the lung. The targeting of DCs was dependent on their ability to directly interact with CTLs through the presentation of antigen on MHC-I, with lung imaging revealing interactions not only with the CD103+ classical cross-presenting DCs, but also in the critical allergy-driving CD11b+ DCs. Therefore, allergen-specific CTLs deplete CD103+ and CD11b+ DC populations in the lung, which in turn reduces allergen presentation to disease-mediating Th2 cells, resulting in amelioration of allergic airway inflammation. Immunotherapy with allergen-specific CTLs thus represents a targeted treatment that may provide new hope in the fight against allergic exacerbations of atopic asthma.
Advisor: Delahunt, Brett; Ronchese, Franca; Connor, Lisa
Degree Name: Doctor of Philosophy
Degree Discipline: Department of Pathology, University of Otago Wellington
Publisher: University of Otago
Keywords: Immunology; asthma; allergy; allergic; airway; inflammation; CTL; cytotoxic; t; cell; DC; Dendritic; cells
Research Type: Thesis