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Celiac disease is a unique organ\u2010specific autoimmune\u2010like disorder occurring in genetically susceptible individuals carrying HLA\u2010DQ2 or HLA\u2010DQ8 molecules who consume gluten. The key histological characteristic of the disease in humans is the destruction of the lining of the small intestine, a feature that has been difficult to reproduce in immunocompetent animal models. This unit describes the DQ8\u2010D<jats:sup>d<\/jats:sup>\u2010villin\u2010IL\u201015 transgenic mouse model of CeD, which was engineered based on the knowledge acquired from studying CeD patients\u2019 intestinal samples, and which represents the first animal model that develops villous atrophy in an HLA\u2010 and gluten\u2010dependent manner without administration of any adjuvant. We provide detailed protocols for inducing and monitoring intestinal tissue damage, evaluating the cytotoxic properties of intraepithelial lymphocytes that mediate enterocyte lysis, and assessing the activation of the enzyme transglutaminase 2, which contributes to the generation of highly immunogenic gluten peptides. Detailed protocols to prepare pepsin\u2010trypsin digested gliadin (PT\u2010gliadin) or chymotrypsin\u2010digested gliadin (CT\u2010gliadin), which allow antibody detection against native or deamidated gluten peptides, are also provided in this unit. \u00a9 2022 The Authors. Current Protocols published by Wiley Periodicals LLC.<\/jats:p><jats:p><jats:bold>Basic Protocol 1<\/jats:bold>: Induction of celiac\u2010like disease in DQ8\u2010D<jats:sup>d<\/jats:sup>\u2010villin\u2010IL\u201015tg mice<\/jats:p><jats:p><jats:bold>Basic Protocol 2<\/jats:bold>: Histological assessment of villous atrophy<\/jats:p><jats:p><jats:bold>Support Protocol 1<\/jats:bold>: Morphometric assessment of villous\/crypt ratio<\/jats:p><jats:p><jats:bold>Support Protocol 2<\/jats:bold>: Evaluation of epithelial cells renewal<\/jats:p><jats:p><jats:bold>Support Protocol 3<\/jats:bold>: Evaluation of the density of intraepithelial lymphocytes<\/jats:p><jats:p><jats:bold>Basic Protocol 3<\/jats:bold>: Analysis of cytotoxic intraepithelial lymphocytes<\/jats:p><jats:p><jats:bold>Basic Protocol 4<\/jats:bold>: Transglutaminase 2 activation and measurement of antibodies against native and deamidated gluten peptides<\/jats:p><jats:p><jats:bold>Support Protocol 4<\/jats:bold>: Preparation of CT\u2010gliadin<\/jats:p><jats:p><jats:bold>Support Protocol 5<\/jats:bold>: Preparation of PT\u2010gliadin<\/jats:p>","DOI":"10.1002\/cpz1.515","type":"journal-article","created":{"date-parts":[[2022,8,22]],"date-time":"2022-08-22T13:50:20Z","timestamp":1661176220000},"source":"Crossref","is-referenced-by-count":14,"title":["A Mouse Model of Celiac Disease"],"prefix":"10.1002","volume":"2","author":[{"given":"Val\u00e9rie","family":"Abadie","sequence":"first","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois"},{"name":"Celiac Disease Center University of Chicago  Chicago Illinois"},{"name":"Section of Gastroenterology, Hepatology and Nutrition University of Chicago  Chicago Illinois"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chaitan","family":"Khosla","sequence":"additional","affiliation":[{"name":"Department of Chemistry Stanford University  Stanford California"},{"name":"Department of Chemical Engineering Stanford University  Stanford California"},{"name":"Stanford ChEM\u2010H Stanford University  Stanford California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bana","family":"Jabri","sequence":"additional","affiliation":[{"name":"Department of Medicine University of Chicago  Chicago Illinois"},{"name":"Celiac Disease Center University of Chicago  Chicago Illinois"},{"name":"Section of Gastroenterology, Hepatology and Nutrition University of Chicago  Chicago Illinois"},{"name":"Committee on Immunology University of Chicago  Chicago Illinois"},{"name":"Department of Pathology University of Chicago  Chicago 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