P086 Glycosylation of T-cells as a new molecular biomarker in inflammatory bowel disease: an opportunity for new therapeutic strategies
A. M. Dias1, M. Pereira1, R. Marcos-Pinto2, A. Correia3, M. Vilanova3, C. Reis1, P. Lago2, S. S. Pinho*1
1IPATIMUP/i3S, University of Porto, Glycobiology in Cancer, Porto, Portugal, 2Porto Centre Hospital, Hospital Santo António, Gastrenterology department, Porto, Portugal, 3Institute of Biomedical Sciences of Abel Salazar (ICBAS), University of Porto, Immunology department, Porto, Portugal
Inflammatory bowel diseases (IBD), such as Crohn´s disease (CD) and ulcerative colitis (UC), are chronic immune-mediated disorders of the gastrointestinal tract. The precise etiopathogenesis of IBD is still unknown, and the disease remains incurable. The current therapeutic strategies for IBD are limited by effectiveness and/or toxicity, and the selection of patients for therapy remains a major challenge. These clinical concerns clearly highlight the need of identifying new molecular biomarkers that improve the therapeutic stratification of patients and are capable of being selectively targeted with new optimised therapies. In the study, we aimed to assess for the first time in IBD, whether glycosylation of T-cells is a yet uncovered factor that tips the balance between homeostasis and intestinal inflammation, and whether it could be a novel targeted-specific mechanism, stimulating the development of new IBD therapies. Additionally, how this novel glyco-biomarker has the potential to predict disease course and help in patients’ therapeutic stratification was also assessed.
The evaluation of the levels and profile of glycosylation of intestinal T-cells were assessed in a cohort of 200 IBD patients (with different clinicopathological features) and healthy controls, using state of the art technical approaches in combination with advanced technology, such as mass spectrometry. The experimental modulation of glycosylation and its effect in the regulation of immune response was assessed both in ex-vivo T lymphocytes purified from fresh colonic biopsies from IBD patients and controls and in different IBD-induced mouse models.
We demonstrated for the first time that the experimental modulation of glycosylation in intestinal T-cells (in ex-vivo T lymphocytes) regulates the adaptive immune response in IBD as demonstrated by the decrease in T-cell proliferation, T-cell signalling, and inhibition of pro-inflammatory cytokines. These results were further validated in mouse models of IBD showing a promising therapeutic applicability of these glycans in the control of intestinal inflammation. Importantly, from the clinical point of view, the levels of glycosylation of T-cells (glyco-biomarker) were significantly correlated with patients’ disease course having also a positive predictive value in IBD patients’ response to therapy.
Overall, these results point towards the identification of a novel molecular biomarker in IBD with positive predictive value in disease course and response to therapy. Additionally, this novel biomarker can be selectively targeted with new and optimised therapeutic strategies.