Abstract
Abstract Crohn’s Disease is characterized by dysregulation of the immune response in the ileum. To study the perturbation of homeostasis within the ileum we utilize a “Bigenic” mouse model combining a TCR transgene and matching transgenic target antigen restricted to ileal crypt expression. Juvenile Bigenic mice experience TH17-associated ileitis and ileal hyperplasia. Antigen transcript is demonstrated to be localized exclusively in ileal crypts, as visualized with in situ hybridization of mRNA. Roughly 50% of Bigenic mice mature and acquire symptomatic phenotype (BigenicS) including colitis and suboptimal growth, while losing ileal hyperplasia. The remaining non-symptomatic Bigenic mice (BigenicNS) retain ileal hyperplasia and successfully build a supply of TH17 and ileal-reactive Treg cells. Previous studies in our lab indicate that IL-17A and INFγ are protective in this Bigenic model – their depletion by antibody binding accelerates disease and hinders accumulation of ileal-reactive Tregs. Furthermore, INFγKO Bigenic mice demonstrate almost complete penetrance of the symptomatic phenotype, with near 100% fatality by 50 days of life. Manipulation of microbiota in juvenile INFγKO Bigenic mice can protect them from this dysregulated state. Administration of a streptomycin/bacitracin antibiotic cocktail ad libitum in drinking water upon initial manifestation of weight loss symptoms or initiated preemptively upon weaning rescues and prevents, respectively, the weight loss phenotype and colitis.
Published Version
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