Ex Vivo Modeling and Pharmacological Modulation of Tissue Immune Responses in Inflammatory Bowel Disease Using Precision-Cut Intestinal Slices

Abstract

Inflammatory bowel disease (IBD) affects approximately 5 million people worldwide, causing chronic inflammation and increased mortality. Despite advances in therapy, the underlying immune mechanisms remain poorly understood, highlighting the need for human-immunocompetent models to enhance translational research. This study aimed to investigate local immune responses using precision-cut intestinal slices (PCIS) from IBD patients and evaluate immunomodulatory treatment directly in patient tissue ex vivo. PCIS from ileal resections of IBD and non-IBD patients were stimulated with Concanavalin A (ConA) or lipopolysaccharide (LPS). Histological analysis of IBD-derived PCIS showed villus atrophy, infiltration of lymphocytes and macrophages, and RNA analysis revealed upregulation of IL-17 and interferon signaling pathways. LPS- and ConA-induced functional immune responses in the tissue, with IBD tissue exhibiting increased levels of specific cytokines compared with non-IBD tissue, including IL-17F and IL-21 after ConA-stimulation, and IL-22 as well as ENA-78 following LPS-stimulation. Pimecrolimus treatment led to a marked reduction in the release of IL-2, IL-17A, and IFN-γ, and inhibited the IBD supernatant-induced reduction in transepithelial electrical resistance. Our data provide the first in-depth characterization of local tissue immune responses in human PCIS, highlighting the potential of this model to study disease-specific immune activity and evaluate pharmacological interventions ex vivo.