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|Title:||EXPLORING NOVEL MECHANISMS AND THERAPIES FOR CELIAC DISEASE|
|Department:||Medical Sciences (Division of Physiology/Pharmacology)|
|Abstract:||The gastrointestinal tract forms the body’s largest interface with the external environment and is exposed to a vast amount of foreign material, including pathogenic and commensal bacteria, as well as food antigens. The gastrointestinal tract has multiple functions that are performed through complex interactions by its different components. It must be able to degrade food, absorb nutrients and eliminate waste, while at the same time maintain a balance between immune tolerance and protection against pathogenic and antigenic material. This concept of mucosally-induced tolerance is a key feature of the gut immune system, whereby a state of local and systemic unresponsiveness to food protein or systemic ignorance of commensal bacteria is maintained under homeostatic conditions through interactions between the host, dietary factors, and the intestinal microbiota. Dysfunctional interactions can lead to a breakdown in tolerance to otherwise innocuous antigens. One of the best characterized food sensitivities is celiac disease (CD). CD is a chronic immune-mediated disease triggered by the ingestion of gluten, the water insoluble protein fraction in wheat, rye and barley, in patients who are HLA/DQ2 or DQ8 positive. Celiac patients can experience a loss of oral tolerance to gluten any time throughout life. The clinical presentation of CD is variable and is often associated with extra-intestinal autoimmune diseases, such as type 1 diabetes (T1D). The increasing incidence of CD and the observation that only a small proportion of genetically susceptible individuals go on to develop active inflammation suggest a role for additional environmental factors in disease pathogenesis. The current treatment for CD is a strict, life-long adherence to a gluten-free diet (GFD), which is very demanding. Frequent gluten contamination can lead to persistent mucosal damage and symptoms, which have a negative effect on quality of life. Understanding the environmental and host factors that contribute to gluten tolerance is critical for the development of adjuvant therapies to the GFD. Therefore, the overall aim of my thesis is to characterize a humanized mouse model of gluten sensitivity in order to study factors that influence host-responses to gluten and to investigate potential therapeutic strategies. In chapter 3 of this thesis I characterized host responses to gluten using transgenic non-obese diabetic (NOD)/DQ8 mice. I found that gluten sensitization in NOD/DQ8 mice induced barrier dysfunction with a moderate degree of enteropathy and the development of anti-gliadin and anti-tissue-transglutaminase antibodies. I also explored the potential role of gluten in the development of T1D and found that gluten-induced barrier dysfunction was not sufficient to induce insulitis; a partial depletion of regulatory T cells (Tregs) plus gluten sensitization was required. In chapter 4, I utilized this model to demonstrate that the microbiota can modulate host responses to gluten. I found that both the presence and absence of a microbiota, as well as the composition of the microbiota influenced host responses to gluten in NOD/DQ8 mice. Finally, Chapters 5 and 6 of this thesis utilized transgenic DQ8 mice to explore two different adjuvant therapies for CD. In chapter 5, I showed that administration of a gluten binding polymer, P(HEMA-co-SS, to gluten-sensitive HLA/DQ8 mice reduced short-term and long-term gluten-induced barrier dysfunction and inflammation. In chapter 6, I discovered that elafin, a human anti-protease, was decreased in patients with active CD and in vitro, it inhibited the deamidation of gliadin peptides, a key step in the pathogenesis of CD. I showed that administration of elafin prevented gluten-induced barrier dysfunction and intraepithelial lymphocytosis. Together these results, (a) provide an in depth characterization of a humanized animal model for studying gluten-induced intestinal and extra-intestinal immune responses, (b) demonstrate the role of the microbiota as an environmental modulator of gluten-induced immune responses, (c) support the preclinical potential of two novel adjuvant therapies to the GFD. These findings emphasize the translational value of using relevant animal models to study the complex interactions between environmental and host factors that contribute to intestinal health and disease.|
|Appears in Collections:||Open Access Dissertations and Theses|
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|PhD Thesis 2015, Galipeau HJ.pdf||Thesis||7.38 MB||Adobe PDF||View/Open|
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