P078 Vedolizumab Treatment of ex-vivo Human Ulcerative Colitis (UC) Explants Results in Altered Inflammatory Protein Secretion Profiles
Corcoran, R.(1);O'Connell, F.(2);O'Sullivan, J.(2);Kevans, D.(1);
(1)St James’s Hospital, Department of Gastroenterology, Dublin, Ireland;(2)Trinity Translational Medicine Institute- Trinity College Dublin, Department of Surgery- Trinity College Dublin- St James’s Hospital- Dublin 8- Ireland, Dublin, Ireland;
Background
Patient-derived inflammatory bowel disease (IBD) ex-plants have potential for biomarker and therapy discovery. Vedolizumab (VDZ) is a monoclonal antibody targeting a4b47 integrin whose mechanism of action is the reduction of inflammatory immune cell trafficking to the intestinal tract. The association between VDZ exposure and treatment response is unclear and appears insufficiently explained by serum levels. For this reason it is hypothesised that VDZ may also have effects at the tissue level.
Methods
We aimed to evaluate the effect of VDZ on inflammatory protein secretion profiles in ex-vivo human ulcerative colitis ex-plants (UC ex-plants).
Patients with UC, undergoing endoscopy, were prospectively recruited. Endoscopic biopsies were collected and UC ex-plants generated as per previously described methods. UC ex-plants were then co-cultured for 24 hours with an IgG control vehicle or VDZ. After 24 hours tissue conditioned media (TCM) from UC ex-plants was collected. TCM secreted protein profiles were quantified using 54 V-plex ELISA (Meso Scale Diagnostics, USA). Secreted cytokine profile were compared between IgG vehicle (control) and VDZ treated ex-plants. P values < 0.05 were considered significant in analyses.
Results
Thirteen patients with UC were included; age (mean, [range]) 45.8 years [30-78], 54% male; disease duration (mean, [range]) 8 [1-24] years; 62% of patients were anti-TNF naïve. Baseline total Mayo score (median [range]) was 6 [0-9]; endoscopic Mayo score (median [range]) was 2 [0-3]. Comparing VDZ with control treatment, 5 of 54 ex-plant secreted proteins differed significantly. GMCSF, IL-16, IL-22, IL-23 and sVCAM-1 secretion were significantly decreased comparing VDZ and control treatments , p < 0.03 for all comparisons.
Conclusion
The predominant mechanism of action of VDZ is the blocking of gut homing pro-inflammatory immune cell trafficking from the peripheral circulation to the intestinal tract. These data demonstrated that VDZ reduces pro-inflammatory protein secretions from UC ex-plants suggesting an additional local effect of this therapy. Further evaluation is required to determine whether a component of VDZ therapeutic effect occurs at the tissue level.