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OP04 Turning sweet in inflammatory bowel disease: glycans as novel immunomodulators of T-cell-mediated immune response

A. Dias1, M. Pereira1, A. Correia1, I. Alves1, V. Pinto1, L. Azevedo2, L. Maia3, R. Marcos-Pinto3, M. Vilanova1, P. Lago3, S. Pinho*1

1Institute for Research and Innovation in Health (i3S), Immunology, Cancer and GlycoMedicine, Porto, Portugal, 2Medical Faculty, Department of Community Medicine, Information and Health Decision Sciences, Porto, Portugal, 3Porto Centre Hospital, Gastroenterology, Porto, Portugal

Background

Mucosal T lymphocytes from patients with ulcerative colitis (UC) were previously shown to display a deficiency in branched N-glycans that was associated with disease severity.1,2 However, whether this altered glycosylation pathway shapes the course of the T-cell response constituting a targeted-specific mechanism in UC remains largely unknown. Moreover, the predictive capacity of this colonic glycosignature in terms of disease course and therapy response was investigated.

Methods

We used a multi-disciplinary approach that gathers in vitro, ex vivo, mouse models of disease and clinical validation in human samples. Human ex vivo CD3+ T cells (from intestinal lamina propria) were purified from fresh colonic biopsies and blood of 75 UC patients with active disease and with different Mayo endoscopic subscores. T cells were cultured and supplemented with increasing doses of the simple glycan N-acetylglucosamine (GlcNAc). The impact on T-cell-mediated immune response was analysed by assessing: T-cell proliferation; T-cell activation and differentiation; cytokine profile; TCR signalling and the glycophenotype of T-cells were also determined. Additionally, colitis were induced (with DSS) in null/heterozygous mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5−/−; MGAT5+/−); treatment with GlcNAc orally and/or with enemas was performed and the immunomodulatory effects of GlcNAc were evaluated.

Results

We demonstrated that metabolic supplementation of ex vivo mucosal T cells from active UC patients with GlcNAc resulted in enhancement of branched N-glycosylation in the T-cell receptor (TCR), leading to suppression of T-cell growth, inhibition of the Th1/Th17 immune response, and controlled T-cell activity. We further demonstrated that mouse models displaying a deficiency in the branched N-glycosylation pathway (MGAT5−/−, MGAT5+/−) exhibited increased susceptibility to severe forms of colitis and early-onset disease. The treatment of these mice with GlcNAc significantly reduced disease severity and suppressed disease progression due to a controlled T-cell-mediated immune response at the intestinal mucosa.3 Furthermore, we also showed that the levels of expression of branched N-glycans analysed in colonic biopsies of UC patients close to diagnosis predicts the failure to standard therapy.4

Conclusion

We propose glycans as novel immunomodulators in IBD, further disclosing a promising predictive glycobiomarker associated with therapy response.

Note: This work was sponsored by ECCO grant 2017.

References

1. Pinho SS, Reis CA. Glycosylation in cancer: mechanisms and clinical implications. Nat Rev Cancer 2015;15:540–55.

2. Dias AM, Dourado J, Lago P, et al. Dysregulation of T cell receptor N-glycosylation: a molecular mechanism involved in ulcerative colitis. Hum Mol Genet 2014;23:2416–27.

3. Dias AM, Correia A, Pereira MS, et al. Metabolic control of T cell immune response through glycans in inflammatory bowel disease. Proc Natl Acad Sci USA 2018;115:E4651–60.

4. Pereira MS, Maia L, Azevedo LF, et al. A (glyco)biomarker that predicts failure to standard therapy in ulcerative colitis patients. J Crohns Colitis 2018. doi:10.1093/ecco-jcc/jjy139.