The prevalence of allergic diseases, such as asthma, rhinitis, eczema and food allergies has increased dramatically over the last few decades and is now a major health and economic burden throughout the developed and developing worlds. Type I (immediate) hypersensitivity reactions are mediated by immunoglobulin E (IgE) responses directed against innocuous environmental antigens, such as pollen, housedust mites or animal dander. It is the resulting release of pharmacological mediators by IgE-sensitised mast cells that cause the symptoms of asthma and allergic rhinitis. The induction of IgE is dependent on CD4+ T cells of the Th2 phenotype which are characterised by the production of specific cytokines (IL-4, IL-5 and IL-13). In contrast, the presence of allergen reactive Thl cells, which secrete IFN-y, in nonallergic healthy individuals suggests that Thl immunity is not damaging to the host and is possibly associated with protective immunity. It is clear with the high incidence of atopic disorders combined with existing treatments, which are in general symptomatic, that there is a requirement for new therapeutic agents. Since CD4+ T cells play an important role in the response to allergens they are an obvious target for drug development and they can be targeted directly, with the aim of inducing specific tolerance. A second strategy for inhibiting the synthesis of Th2 cytokines may be achieved by promoting the induction of Thl immunity. Therefore, the main aim of this study was to investigate these different approaches for the modulation of Th2 immunity to the major house dust mite allergen Der p 1. Tolerance induction or the promotion of Thl responses were attempted by intranasal delivery of antigen alone, by the systemic or mucosal delivery of Der p 1 in PLG polymer microparticles (MEA) and finally, by intranasal administration with chitosan, an enhancer of epithelial permeability. In order to investigate the efficacy of the regimens of vaccination, an adjuvant free model of Th2 cytokine-mediated allergic inflammation was developed in vivo in H-2b mice. Vaccination with microencapsulated antigen failed to elicit a Thl response or induce tolerance despite altering the kinetics, dose and method of delivery. In fact, the Th2 phenotype was usually exacerbated following administration of MEA/Der p 1 particles. Intranasal co-administration of antigen with chitosan inhibited Th2 cytokine production but not as a result of the tolerance induction. Similarly, high doses of soluble peptide delivered intranasally, failed to tolerise allergen-specific Th2 immunity. In conclusion, the redirection of the Th2 immune response and the induction of tolerance were difficult to achieve. However, chitosan which was not as extensively researched as the other approaches may prove to be of therapeutic value.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:726375 |
| Date | January 2003 |
| Creators | Hall, Gillian |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/24666 |
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