P033 Combination of vedolizumab with tacrolimus is more efficient in reducing intestinal inflammation than vedolizumab alone in the DSS-induced acute colitis mouse model
R. Manzini, K. Atrott, M. Schwarzfischer, A. Laimbacher, S. Lang, G. Rogler, M. Scharl, M.R. Spalinger
Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland
Background
The humanised monoclonal antibody vedolizumab is used in the treatment of ulcerative colitis (UC) and Crohn’s disease (CD). Vedolizumab reduces intestinal inflammation through inhibition of the integrin heterodimer α 4β 7, responsible for the homing of T cells to the intestinal mucosa. Recent studies have also shown a possible involvement of vedolizumab in the regulation of the innate immune system. Particularly in CD, only a fraction of patients respond to vedolizumab treatment, and combination therapy with immunosuppressant drugs, such as the calcineurin-inhibitor tacrolimus, might prove beneficial. The aim of this study was to assess if co-treatment of vedolizumab and tacrolimus is more efficient in reducing intestinal inflammation in an acute colitis mouse model and to unravel the underlying molecular mechanisms.
Methods
NOD-SCID-SGM3 mice were reconstituted with human CD34+ cells and treated with 3% dextrane sodium sulphate (DSS) in drinking water to induce acute colitis. Mice were treated with vedolizumab alone (30mg/kg, inject 3 days prior to DSS-start and 50mg/kg at day 0 and at day 4 of DSS-treatment), tacrolimus alone (1mg/kg/day intraperitoneally), or a combination of tacrolimus and vedolizumab during colitis induction.
Results
As expected, DSS-treatment induced colitis in mice as observed by weight loss, diarrhoea, colon shortening, and endoscopic signs of inflammation categorised by the MEICS score. This translated histologically to an increased immune cell infiltration and epithelial erosion. Vedolizumab and tacrolimus treatment alone did not significantly reduce colitis severity, although endoscopy showed slightly less severe inflammation in vedolizumab-treated mice. Combination of vedolizumab and tacrolimus, however, clearly reduced colonoscopy and histology scores. DSS-treatment increased the number of CD3 T cells and CD68 macrophages in the intestine, an effect counteracted by vedolizumab or tacrolimus alone and further pronounced by combination treatment. Particularly vedolizumab treatment, either alone or in combination, caused clear reduction of pro-inflammatory M1 macrophages. Additionally, vedolizumab alone or combined decreased the levels of intestinal epithelial cell apoptosis as indicated by staining for cleaved caspase-3.
Conclusion
Our data demonstrate that the anti-inflammatory effect of vedolizumab is potentiated by co-treatment with tacrolimus. Notably, the combination of both drugs was more efficient in reducing T-cell and macrophage infiltration into the intestine. This indicates that the combination of vedolizumab with immunosuppressant drugs might prove beneficial for patients that do not respond to vedolizumab-only therapy.