P162 Comparative effectiveness of vedolizumab and ustekinumab in anti-TNF refractory Crohn’s disease: Multi-centre retrospective cohort study

Abstract

role than previously thought. We have now investigated whether IKKa represents a potential therapeutic target for IBD using murine epithelial intestinal organoids. Methods Intestinal crypts were harvested from C57BL/6J mice (n=3) and cultured into enteroids in 3D using a Matrigel matrix. Enteroids were either untreated or administered 0.6 mM of IKKa inhibitor SU1433 on day 3 after passage and stimulated with 30 ng/ml TNF on day 4. Enteroid morphological changes were assessed daily using the Enteroid Circularity Score. Immunohistochemistry for active caspase-3 and Ki-67 was performed to assess apoptosis and cell proliferation. Enteroids were harvested at 3, 6, 24, and 48 hours after stimulation and RT-qPCR was performed to determine the expression profiles of selected inflammation-related and non-canonical NF-kB related target genes.Results Enteroids pre-treated with SU1433 and then stimulated with TNF were protected against enteroid rounding compared to TNF treatment alone. There was also a marked decrease in active caspase-3 positive apoptotic cells 48 hours following TNF in the SU1433 pre-treated group compared to the TNF only group. At the 3, 6, 24 and 48 hour time points NF-k B2, TNF, CXCL9 and ICAM-1 expressions were significantly increased compared to TNF-naïve groups, however there was no significant difference between the SU1433+TNF and TNF only treatment groups. Conclusions TNF induced enteroid rounding and promoted the expressions of several inflammation related genes in the NF-kB signalling pathways. Pharmacological inhibition of IKKa prevented TNF-induced enteroid rounding. This was associated with a significant decrease in apoptosis on histology. Together, our findings suggest that IKKa may be a potential therapeutic target for the prevention of IBD relapse.