Generating Transgenic Mouse Models for Studying Celiac Disease

Abstract

This chapter provides a brief overview of current animal models for studying celiac disease, with a focus on generating HLA transgenic mouse models. Human Leukocyte Antigen class II molecules have been a particular target for transgenic mice due to their tight association with celiac disease, and a number of murine models have been developed which had the endogenous MHC class II genes replaced with insertions of disease susceptible HLA class II alleles DQ2 or DQ8. Additionally, transgenic mice that overexpress interleukin-15 (IL-15), a key player in the inflammatory cascade that leads to celiac disease, have also been generated to model a state of chronic inflammation. To explore the contribution of specific bacteria in gluten-sensitive enteropathy, the nude mouse and rat models have been studied in germ-free facilities. These reductionist mouse models allow us to address single factors thought to have crucial roles in celiac disease. No single model has incorporated all of the multiple factors that make up celiac disease. Rather, these mouse models can allow the functional interrogation of specific components of the many stages of, and contributions to, the pathogenic mechanisms that will lead to gluten-dependent enteropathy. Overall, the tools for animal studies in celiac disease are many and varied, and provide ample space for further creativity as well as to characterize the complete and complex pathogenesis of celiac disease.

Celiac disease: a comprehensive current review

“…These data shed light on the molecular mechanisms underlying CD histopathology and illuminate the reason for the lack of enteropathy in the mouse models for CD. Indeed, lack of consistent CD-like enteropathy in humanized mice [61] supports the concept that the accelerated disruption of enterocytes secondary to the adaptive CD4 + T cell insult cannot fully explain CD pathogenesis, supporting the notion that an intrinsic defect of the stem cell compartment in subjects at risk of CD is a key element of CD enteropathy [60, 62].…”

T lymphocytes in the intestinal mucosa: defense and tolerance

“…In one transgenic mouse model, endogenous MHC class II genes are replaced with the disease-susceptible HLA class II alleles DQ2 or DQ8, leading to an abnormal antigen presentation to T cells. 100,101 In addition, transgenic mice overexpressing interleukin-15 (IL-15), resulting in an accumulation of IELs in the intestine, have also been used to generate a model of chronic inflammation. 102 Furthermore, environmental factors, such as intestinal microbes, also contribute to the pathogenesis of celiac disease.…”

Review article: exposure to microbes and risk of coeliac disease

“…Animal models of gluten enteropathy have elucidated potential mechanisms, though these models are different from human CD in several important aspects 171 . Experimental infections with reovirus induced increased signalling by type I interferons.…”