P149 TARGETING OF THE INTESTINAL GLYCAN SLEA INCREASES BARRIER INTEGRITY, REDUCED INFLAMMATION DURING COLITIS AND IMPROVES COLONIC MUCOSAL WOUND HEALING. (7th February 2019)

• Record Type: Journal Article
• Authors: Kelm, Matthias; Cummings, Richard D; Parkos, Charles A; Brazil, Jennifer C
• Is Part Of: Inflammatory bowel diseases. Volume 25(2019)Supplement 1
• Page Start: S67
• Page End: S67
• Publication Date: 2019-02-07
• Subjects: Inflammatory bowel diseases -- Periodicals; Colitis, Ulcerative -- Periodicals; Crohn Disease -- Periodicals; Inflammatory Bowel Diseases -- Periodicals; 616.344
• DOI: 10.1093/ibd/izy393.166
• Languages: English
• ISSNs: 1078-0998

Abstract

Abstract: Dysregulated neutrophil (PMN) trafficking into the mucosa and associated tissue damage is a pathological hallmark of numerous human diseases including inflammatory bowel disease (IBD). In addition to excessive trafficking of PMN, mucosal inflammation is also associated with specific alterations in cellular glycosylation. Glycans represent highly accessible binding epitopes that decorate key epithelial and PMN glycoproteins involved in the regulation of PMN transepithelial migration (TEpM) and epithelial function. Using the novel monoclonal antibody (mAb) GM35, we have identified sialyl Lewis A (sLe a ) as an inflammation induced glycan that decorates the apical epithelial glycoprotein CD44v6. Further, sLe a on CD44v6 can be targeted with GM35 to block shedding of the extracellular domain of CD44v6 and inhibit PMN intestinal trafficking in vitro and in vivo . Here we show that in addition to inhibiting PMN TEpM, targeting of sLe a increases epithelial integrity and recovery from barrier disruption in vitro. Further, immunoblotting analyses suggest that these protective effects on barrier are mediated through deactivation of Akt (a kinase previously shown to destabilize epithelial adherens junctions) downstream of sLe a engagement. Treatment of C57BL/6J mice with GM35 followed by induction of colitis with dextran sodium sulfate resulted in decreased weight loss and composite disease activity scores compared to mice treated with an isotype control mAb. Finally, injection of GM35 directly into biopsy-induced colonic ulcers resulted in improved mucosal wound healing in vivo. Therefore, sLe a represents a rational target for amelioration of PMN-mediated tissue damage, regulation of intestinal epithelial barrier function and more rapid resolution of mucosal inflammation in IBD.