CHARACTERIZATION OF A NOVEL MODEL OF GLUTEN SENSITIVITY

Abstract

The gastrointestinal tract forms the largest mucosal interface between the host and the external environment and is therefore exposed to antigens from food and microbes as well as nutrients and environmental toxins. Gut functions necessary for the survival of the host, such as digestion and nutrient absorption, must be completed while ensuring protection from pathogenic microorganisms and potential toxins. This is achieved through highly coordinated interactions between the intestinal barrier, the gut immune system, neuromotor and endocrine systems, and the gut microbiota. An example of breakdown in this balance is celiac disease (CeD), an immune mediated enteropathy that is triggered by the ingestion of gluten proteins by individuals that carry either the HLA-DQ8 or DQ2 allele. Currently, the only treatment for CeD is a strict, lifelong gluten free diet and drug development in CeD has been delayed due to a lack of preclinical models. Further, most preclinical murine models are based on the expression of the HLA-DQ8 allele, the CeD risk allele that is carried by only 10% of patients. Therefore, the overall goal of my thesis is to characterize a model of gluten sensitivity based on the transgenic expression of the HLA-DQ2 allele. In Chapter 3 of this thesis, I characterized the physiological and immunological response to gluten using transgenic DR3-DQ2 mice. I determined that following gluten sensitization and an acute challenge, DR3-DQ2 mice developed a moderate level of enteropathy, anti-tissue transglutaminase 2 and anti-gliadin antibodies, and had increased il15 expression. In Chapter 4 of this thesis, I explored the impact of gluten sensitization and a long-term exposure to gluten using DR3-DQ2 mice. I demonstrated that without gluten sensitization, DR3-DQ2 mice spontaneously begin to develop anti-tissue transglutaminase antibodies, mild enteropathy, and increased paracellular permeability when exposed to gluten for a longer period of time. Together, the findings in both Chapter 3 and Chapter 4, show that mice transgenic for the DR3-DQ2 haplotype mimic different responses to gluten seen in CeD patients and will be a valuable tool in preclinical CeD research in the future. These findings also show the importance of utilizing a well-defined model to study the complex interactions between the host, immune system, and microbiota in the context of CeD.