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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.

Allergic disease encompasses multiple complex syndromes including hayfever, food allergies, eczema and asthma. Atopy is the genetic predisposition towards an IgE-driven immune response in reaction to environmental stimuli, and often serves as a predictor for the development of allergies in the future. While disease etiology is not yet fully understood, many factors including genetics and the environment play a role in the development of allergic disease. Reliable methods for predicting atopic disease development are crucial in emerging therapeutic approaches, which aim to decrease allergic disease severity and clinical progression through early detection and preventative measures. While DCs are emerging as key players in the development of allergic disease, they are challenging to study in vivo due to their low numbers, and ex vivo methods remain relatively unstudied. In this project, receptor expression profiles of atopic-at-risk infants compared to not-atrisk infants were examined in DCs found in cord-blood at birth and CD34+-derived DCs cultured ex vivo. Atopic-at-risks exhibited a higher percentage of ex vivo pDCs expressing TSLPR when compared to not-at-risks. Additionally, an increase of FcεRI expression in atopic-at-risks was found approaching significance in in vivo mDCs. Furthermore, DC differentiation in culture from hematopoietic progenitors and the differences between in vivo and ex vivo DCs were studied. Results indicated a consistent 10-fold increase in the DC population after a 12-day culture compared to cord blood DC numbers. Additionally, a distinct DC population emerged as early as Day 3 with a substantial increase in the percentage of mDCs relative to pDCs. A trend of increased TSLP, CD80, CD86 receptor expression and decreased TLR-5, ST2, FcεRI receptor expression after culture in both mDCs and pDCs was also noted. / Thesis / Master of Science (MSc) / Allergic disease development typically begins in infancy, progressing classically in a series of stages from early life through adulthood. Currently, there is a lack of reliable predictive tests for the development of atopic sensitization and disease. This has slowed efforts to intercept and prevent allergy development at its earliest stages. Dendritic cells (DCs) link innate and adaptive immunity and are thought to be key players in the development of allergic disease. However, the low numbers of DCs in blood make them challenging to study. Methods such as inducing the differentiation of DCs from progenitors are often utilized to obtain a sufficient number of cells. This project investigates whether receptor expression of cord blood-derived DCs grown ex vivo are comparable to the profiles of in vivo DCs at birth. Furthermore, the expression of key receptors on DCs grown in vivo/ex vivo are compared in atopic at-risk, not-at-risk infants.

Mites are endemic and allergy to mite excreta and parts is one of the most common allergies. Health care practitioners have recommended the removal of carpets from homes of people with mite allergies. Little, if any, consideration is given to the fact that some persons may benefit directly from the presence of carpet in their homes. In the allergen and mite research literature, carpets are rarely described as having unique characteristics and are generally referred to as a generic entity. Carpets, however, do have unique characteristics that define their construction, appearance, wearability, and cleanability. Seventy-two pieces of commercially available, residential flooring materials were inoculated with identical numbers of mites, Dermatophagiodes farinae, and placed in the Textiles Conditioning Lab at Virginia Tech. The mites and carpet pieces were maintained in the lab, under identical, environmentally controlled conditions for 6 weeks, then the mites were extracted and counted. On the basis of the results of statistical tests run on the study data, the null hypothesis, that there is no difference between the numbers of mites grown on the different flooring conditions, was rejected. Statistically significant differences exist between the hard floor and the nylon carpet, between hard floor and olefin carpets, but no difference between hard floor and wool carpet. Nylon was the carpet fiber that was most supportive of the growth of house dust mites, olefin was the second most supportive, and wool carpet and hard floor were similar in being the least supportive. / Master of Science

Yes / Hymenoptera venom allergy is a potentially life‐threatening allergic reaction following a honeybee, vespid, or ant sting. Systemic‐allergic sting reactions have been reported in up to 7.5% of adults and up to 3.4% of children. They can be mild and restricted to the skin or moderate to severe with a risk of life‐threatening anaphylaxis. Patients should carry an emergency kit containing an adrenaline autoinjector, H1‐antihistamines, and corticosteroids depending on the severity of their previous sting reaction(s). The only treatment to prevent further systemic sting reactions is venom immunotherapy. This guideline has been prepared by the European Academy of Allergy and Clinical Immunology's (EAACI) Taskforce on Venom Immunotherapy as part of the EAACI Guidelines on Allergen Immunotherapy initiative. The guideline aims to provide evidence‐based recommendations for the use of venom immunotherapy, has been informed by a formal systematic review and meta‐analysis and produced using the Appraisal of Guidelines for Research and Evaluation (AGREE II) approach. The process included representation from a range of stakeholders. Venom immunotherapy is indicated in venom‐allergic children and adults to prevent further moderate‐to‐severe systemic sting reactions. Venom immunotherapy is also recommended in adults with only generalized skin reactions as it results in significant improvements in quality of life compared to carrying an adrenaline autoinjector. This guideline aims to give practical advice on performing venom immunotherapy. Key sections cover general considerations before initiating venom immunotherapy, evidence‐based clinical recommendations, risk factors for adverse events and for relapse of systemic sting reaction, and a summary of gaps in the evidence. / European Union's Seventh Framework Programme FP7. Grant Number: 601763