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P036 Expression of CD69 on peripheral lymphocytes predicts treatment response in Acute Severe ulcerative colitis

M. C. Choy*1,2,3, J. Yu2, M. Congiu2, P. Pelpola2, J. Nigro2, R. Burder1, K. Boyd1, M. McGuckin4, A. J. Corbett5, L. Kjer-Nielsen5, J. McCluskey5, K. Visvanathan2, P. De Cruz1,3

1Austin Health, Gastroenterology, Heidelberg, Australia, 2St Vincent's Hospital, Immunology Research Centre, Fitzroy, Australia, 3Austin Academic Centre, University of Melbourne, Medicine, Heidelberg, Australia, 4University of Melbourne, Department of Medicine, Dentistry and Health Sciences, Parkville, Australia, 5The Peter Doherty Institute for Infection and Immunity, University of Melbourne, Department of Microbiology and Immunology, Parkville, Australia

Background

Disease severity in acute severe ulcerative colitis (ASUC) is currently assessed using clinical and endoscopic indices, and treatment response is determined following a trial of drug therapy. Immune profiling potentially offers new methods of classifying disease activity to determine the likelihood of a response to therapy. CD69 is a marker of lymphocyte activation and recent work implicates it in the regulation of intestinal inflammation, with CD69 expression on mucosal associated invariant T (MAIT) cells correlating with IBD disease activity. We aimed to identify biomarkers of steroid and infliximab (IFX) response by immune profiling of peripheral blood and intestinal mucosa.

Methods

Peripheral blood and mucosal biopsies were collected from 44 patients with ASUC on admission and 10 healthy controls. Clinical response to intravenous steroids and IFX salvage therapy was correlated with peripheral lymphocyte CD69 expression, and membrane TNF (mTNF) expression on monocytes measured by flow cytometry, and mucosal cytokine gene expression by RT-PCR.

Results

ASUC patients had a peripheral deficiency of MAIT, natural killer (NK), NKT and Th1 cell proportions compared with healthy controls. CD69 expression on these lymphocytes correlated with disease activity; with CD69 expression on MAIT and NK cell correlating more consistently across clinical, biochemical and endoscopic indices compared with CRP or albumin alone. CD69 expression on MAIT, NK, NKT, Th1, and Th2 cells was significantly higher in steroid non-responders and was predictive of steroid non-response [MAIT (AUROC 0.76, p = 0.01, cut-off 27.55%), NK (AUROC 0.81, p < 0.01, cut-off 16.75%), NKT (AUROC 0.71, p = 0.04, cut-off 33.1%), Th1 (AUROC 0.75, p < 0.01, cut-off 1.23%) and Th2 (AUROC 0.80, p < 0.01, cut-off 5.99%)]. Elevated Th2 CD69 expression also predicted IFX non-response (AUROC 0.74, p = 0.03, cut-off 6.75%) and was an independent immunological predictor of treatment response on multi-variate logistic regression. IFX non-responders had a nonsignificant trend towards higher mTNF expression on monocytes and subsets. Monocyte subset proportions and concomitant mTNF expression did not correlate with steroid response status. Mucosal TGF β expression in IFX non-responders was significantly higher compared with responders (p = 0.03). Mucosal TNF expression was not associated with treatment response or disease activity.

Conclusion

In ASUC, CD69 expression on key peripheral lymphocyte subsets is a novel biomarker of disease severity and has the potential to identify those at risk of treatment failure. Future work is required to discern the function of CD69 in ASUC, to assess why elevated expression is associated with treatment failure, and whether CD69 represents a potential therapeutic target in the future.