Patient-Derived Intestinal Organoids for Diagnosis and Drug Screening of Celiac Disease

Patients with celiac disease have a pathological reaction to gluten and have either HLA-DQ2+ (90%) or HLA-DQ8+, but expression of these MHC class II haplotypes is not sufficient and other factors are necessary for the development of celiac sprue. Diagnosis of celiac disease is determined by presence of transglutaminase 2 (TG2) autoantibody and histology of intestinal biopsies. However, those seeking diagnosis often already maintain a gluten-free diet prior to gastroenterology consultation and therefore test negative for autoantibody and present normal duodenal mucosa. So, it is necessary to have patients receive a gluten-rich diet for weeks to obtain a definitive diagnosis. Celiac patients will thus experience symptoms including diarrhea, bloating, and abdominal pain. Air-liquid interface (ALI) organoids enable culturing epithelium and stroma to recapitulate the human small intestine, and patient-derived organoids can be used for suspected celiac patient diagnosis instead. ALI organoids could be used whether the individual is on a gluten-free diet or gluten-rich diet. Specifically, ALI organoids will be challenged with gliadin and examined for gliadin presentation, immune cell expansion and activation, and epithelial cell death. It could also be used to screen the potency of drug candidates by evaluating the reduction of gliadin-dependent immune cell activation or expansion and epithelial cell death.