Asthma is defined as reversible airflow obstruction and an estimated 1-in-3 Canadians will be diagnosed over their lifetime. Many clinical phenotypes of asthma exist, but allergic asthma is the most common presentation. Despite effective therapies, approximately 65% of Canadian asthmatics have poorly controlled disease. Thus, there remains pressing need to develop disease modifying therapies.
Allergen-specific immunotherapy (SIT) is a disease-modifying therapy for allergic disease that consists of repeatedly administering doses of allergen, to an allergic individual; over 100 years of clinical use, SIT has been demonstrated to reduce symptoms of disease both during and after cessation of therapy. Widespread clinical uptake of SIT has been limited by the risk of developing anaphylaxis as a response to therapy. Peptide immunotherapy is a derivation of SIT, that attempts to retain the disease-modifying benefits, while lessening the risk of anaphylaxis, by treating subjects with allergen-derived T-cell peptide epitopes. Peptide immunotherapy has been demonstrated to reduce symptoms of allergic disease in treated subjects; however, it remains unknown how administration of a single (or several) T-cell epitopes can modulate immune responses to entire complex allergens. Additionally, how genetic diversity in peptide epitope presentation effects the development of immune tolerance is unknown. In this thesis, we sought to characterize these mechanisms of peptide immunotherapy; the hypothesis was, “The induction of immunosuppression by peptide immunotherapy involves the infectious spread of tolerance beyond the treatment epitope, and is dependent upon treatment peptide dose and affinity to MHC”.
Through the definition of these mechanistic traits we hoped to expedite and inform the design of future peptide based therapeutics. The studies presented within this thesis examine the
topic of immune modulation of allergic disease in mouse models, and have focused upon broadly pertinent characteristics of immune modulation, such as the number, dose and affinity of immunomodulatory epitopes. / Thesis / Doctor of Philosophy (PhD) / Asthma is a disease of the airways that can cause difficulties in breathing. In some people, asthma develops because their immune system reacts in an uncontrolled manner to common environmental proteins, called allergens. Whole allergen immunotherapy is a treatment for asthma, where asthmatic people are injected with doses of allergen until their immune system no longer responds to (or ‘tolerates’) the allergen. In some people, injection of allergen can lead to a life-threatening immune response known as ‘anaphylaxis’. Peptide-immunotherapy is a form of whole allergen immunotherapy where people are given small fragments of the allergen (a ‘peptide’) rather than the whole allergen. The benefit of peptide immunotherapy is that the treatment peptides are too small to cause anaphylaxis, but remain large enough to teach the immune system. In this thesis, we examined how treatment with small peptides teaches the immune system to tolerate the larger and more complex whole allergen.
| Identifer | oai:union.ndltd.org:mcmaster.ca/oai:macsphere.mcmaster.ca:11375/22854 |
| Date | January 2018 |
| Creators | Moldaver, Daniel |
| Contributors | Larche, Mark, Medical Sciences (Molecular Virology and Immunology Program) |
| Source Sets | McMaster University |
| Language | English |
| Detected Language | English |
| Type | Thesis |
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