P074 Interferon-γ promotes antigen processing and presentation pathway in the intestinal epithelium of patients with Crohn’s disease

Abstract Background Interferon-γ (IFN-γ) is a major driver of excessive immune response, leading to intestinal mucosal damage and contributing the pathogenesis Crohn’s diseases (CD). In contrast inflammatory cells system, IFN-γ-induced cellular responses has not been well documented in epithelium. The epithelium consists multiple cell types patient-derived organoid model may be appropriate evaluate epithelial patients with CD. Methods To IFN-γ-mediated responses, human small organoids (enteroids) derived from controls (n=6) disease (CD, n=10) were constructed. We focused on death mechanism upregulated CD enteroids validated them surgically resected intestine active Results As concentration IFN-γ increased culture medium, organoid-forming efficiency decreased steadily, which did differ between control enteroids. enteroid viability measured using MTT was estimated 83.10 pg/ml for EC50. treated 100 IFN-γ, PANoptosis main mechanism. Bulk single-cell RNA sequencing revealed that induced expression MHC class II-associated genes, co-inhibitory molecule CD274 (PD-L1), IDO1 enteroids, associated peripheral tolerance absence exogenous antigens. Gene set enrichment analysis identified an up-regulated antigen processing presentation pathway I molecules IFN-γ-treated compared (normalized score=2.13, p=0.002, q=0.005). could result T cell-mediated cytotoxicity selective JAK1 inhibitor, upadacitinib, inhibited HLA-A B higher inflamed than those ischemic enteritis. Conclusion promotes CD, induce cytotoxicity, contribute development