P0053Biologic therapy remodels the immune landscape in IBD leading to altered macrophage phenotypes

Abstract Background Inflammatory Bowel Disease (IBD) is a chronic relapsing inflammatory disease of the gastrointestinal tract that is closely related to immune dysfunction. Macrophages are the key gatekeepers of intestinal immune homeostasis and have a vital influence on IBD. Macrophages are functional plasticity cells which phagocytose and acquire pro- (M1-like) or anti-inflammatory (M2-like) phenotypes according to their microenvironment. Current evidence suggests a causal link between defects in the resolution of intestinal inflammation and altered monocyte-macrophage differentiation in IBD and therefore macrophages gave been considered as a novel potential target to develop new treatment approaches. We aimed to further investigate macrophage function in IBD. Methods Patients with IBD, undergoing endoscopy, were prospectively recruited. Endoscopic biopsies were collected from the sigmoid colon and IBD ex-plants generated as per previously described methods. IBD explants were then co-cultured for 24 hours with an IgG control vehicle, Infliximab (IFX), Ustekinumab (UST) and Vedolizumab (VDZ). After 24 hours, tissue conditioned media (TCM) from IBD explant were collected. Macrophages were isolated from peripheral blood mononuclear cells (PBMCs) from healthy donors. Macrophages were polarised to either M1 or M2 phenotype using previously described methods. Macrophages were then exposed to IBD explant TCM and results analysed using GraphPad Prism. Results 36 patients with IBD were included, 19 had Crohn’s disease (CD) and 17 had ulcerative colitis (UC). Undifferentiated macrophages exposed to TCM from CD and UC patients demonstrated significant M0 variation for both pro- and anti-inflammatory markers with IFX and VDZ drug treatments. M2 phenotype showed significantly decreased expression of anti-inflammatory markers TREM1, CD11b, CD163 and CD206, CD163/CD206 when exposed to VDZ-treated CD TCM but not to UST or IFX-treated TCM. There was no significant difference in any M1 polarised macrophage anti-inflammatory markers with UST or IFX-treated TCM. M1 and M2 polarised macrophages did not show any difference in expression levels of pro or anti-inflammatory on exposure to either IFX or UST-treated UC TCM. However, decreased TREM1 expression was observed in the both the M1 and M2 setting following exposure to VDZ-treated UC TCM. Conclusion Macrophage biology differs between UC and CD patients. In this study VDZ use in both CD and UC TCM and IFX in CD TCM altered macrophage phenotype. Further studies are required to elucidate the nature of biologic therapies effect on immune cells in the tissue microenvironment and whether this can be exploited for therapeutic gain. Conflict of interest: Dr. Corcoran, Roisin: No conflict of interest O’Connell, Fiona: No conflict of interest Kevans, David: No conflict of interest O’Sullivan, Jacintha: No conflict of interest