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PTH-060 Expression of madcam-1 in the upper gastrointestinal tract: is there a role for disrupting interactions between madcam-1 and alpha-4/beta-7 integrin in upper gi crohn’s disease?
  1. A Ahmed1,
  2. DM Pritchard,
  3. MD Burkitt
  1. Cellular and Molecular Physiology, University of Liverpool, Liverpool, UK

Abstract

Introduction MAdCAM-1 is expressed on the endothelial surfaces of intestinal blood vessels. Interaction between MAdCAM-1 and α4β7-integrin regulates intestinal lymphocyte recruitment and trafficking. Therapies targeting this interaction are licensed for use in Crohn’s disease (CD). Although intestinal expression of MAdCAM-1 is well established, its expression in the upper GI tract (UGIT) has been subject to little investigation, and may be relevant in the management of CD patients who have UGIT involvement.

We investigated expression of MAdCAM-1 in Helicobacter felis induced murine gastric inflammation, a model of minimally-inflamed gastric metaplasia (MIGM), and in cancer associated, microscopically normal human colon and oesophagus.

Method To induce MIGM, groups of 5 female C57BL/6 (WT) mice were treated with tamoxifen (TAM) 150 mg/kg or vehicle by IP injection. Animals were culled 72 hours later. Gastric inflammation was studied in groups of 5 INS-GAS mice exposed to sham-gavage, or colonised with H. felis for 6 weeks. Samples of gastric corpus (GC) and forestomach (FS) were obtained for histology.

Liverpool Bio-Innovation Hub Biobank provided sections of histologically normal full-thickness tissue from patients undergoing resections for oesophageal squamous cell carcinoma (oesophagus n=5, GC n=1) or colorectal cancer (n=5) following ethical review. Sections were immunostained for MAdCAM-1; positively stained structures were quantified per unit area.

Results Untreated WT mice demonstrated MAdCAM-1 staining density of 15.0 (±6.4 SD) structures/mm2 in the GC; staining was 7.6 fold more dense in submucosa cf mucosa (p=0.008). MAdCAM-1 staining density increased in mucosa (5.0 fold, p=0.008), but not submucosa after TAM administration. Untreated INS-GAS mice had lower GC MAdCAM-1 staining density than untreated WT mice (4.2 fold, p<0.004). H. felis infection resulted in upregulation of MAdCAM-1 expression in mucosa (21.2 fold, p=0.0159), but not submucosa. In a single section of human GC, MAdCAM-1 was expressed (staining density 3.7). Mean MAdCAM-1 staining density of human colon tissue was 22.45 (±4.4), and staining density was higher in mucosa than submucosa (2.7 fold, p=0.04).

MAdCAM-1 staining was not observed in association with the squamous epithelium of murine FS or human oesophagus, which was significantly different from control columnar epithelial tissues (p=0.0008, p=0.016 respectively).

Conclusion Mucosal MAdCAM-1 expression in murine GC is upregulated during inflammation and tissue remodelling. MAdCAM-1 was not identified in murine or human squamous epithelium. Further studies in cohorts of CD patients are needed to determine whether targeting MAdCAM-1/α4β7-integrin interactions is useful for patients with upper GI CD.

Disclosure of Interest None Declared

  • MAdCAM-1
  • Oesophagus
  • Stomach
  • α4β7-integrin

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