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P229 AlphaE (±E) integrin protein and gene expression are augmented in the ileum relative to the colon in Crohn's disease

R. Ichikawa1, J. Eastham-Anderson1, A. Scherl1, G.W. Tew*1, J.G. Egen1, C.A. Lamb2, 3, J.C. Mansfield3, J.A. Kirby3, W.A. Faubion4, S. O'Byrne1, M.E. Keir1

1Genentech, ITGR Diagnostic Discovery, South San Francisco, United States, 2Newcastle University, Department of Gastroenterology, Newcastle Upon Tyne, United Kingdom, 3Newcastle University, Institute of Cellular Medicine, Newcastle Upon Tyne, United Kingdom, 4Mayo Clinic, Division of Gastroenterology & Hepatology, Rochester, United States

Background

Etrolizumab, a monoclonal antibody against β7 integrin, targets both α4β7 and αEβ7 expressing cells. αE integrin-expressing cells, the majority of which are T cells, are found throughout the gastrointestinal tract mucosa and can localize to the epithelium and lamina propria (LP). αE showed promise as a predictive biomarker for response to etrolizumab in a phase II trial with ulcerative colitis patients. To better understand αE expression in Crohn's disease (CD), we examined the prevalence and localization of αE+ cells and total αE gene expression in the ileum and colon of non-IBD (inflammatory bowel disease) controls and CD patients.

Methods

Ileal and colonic tissue were collected from controls and CD patients. αE+ cells, detected by immunohistochemistry, were counted by an automated algorithm that determines cellular localization relative to intestinal crypts and normalized to total cell counts in respective tissue compartments (mucosa, epithelium and LP). Lymphoid aggregates and Peyer's patches were excluded from analysis. Gene expression was assayed by qRT-PCR in control biopsies and in paired mucosal biopsies from inflamed and uninflamed regions of the colon and ileum from CD patients. Statistical test Kruskal-Wallis was used in analyses.

Results

In control and CD resections, significantly more αE+ cells were present in ileal than in colonic mucosa (Table 1), with significantly more αE+ cells present in ileal than in colonic LP (Table 1); in contrast, the numbers of crypt epithelium-associated αE+ cells were equivalent in both anatomical regions (Table 1). Consistently, αE gene expression levels were significantly higher in ileal than in colonic biopsies in both controls and CD (Table 1). Analysis of paired biopsies from CD patients showed no increase in αE gene expression in inflamed biopsies compared with uninflamed biopsies taken from either the ileum or colon.

Conclusion

These Results demonstrate that in both controls and CD, the number of αE+ cells and αE gene expression levels are increased in the ileum compared to the colon, and this anatomical observation is unaffected by inflammatory status. Furthermore, the greater number of αE+ cells and higher gene expression levels are entirely attributable to increased cell counts in the ileal LP, as both anatomical locations had equivalent crypt epithelial-associated αE+ cell counts. Further studies will be required to examine the role of αE+ cells in CD and whether αE may offer value as a predictive biomarker for response to etrolizumab.

 

“Table 1” Increased αE+ Cell Numbers and Gene Expression Levels in the Ileum vs the Colon of Patients with Crohn’s Disease and Non-IBD Controls

ECCOJC jju027 P229 F0001