MLN3126, an antagonist of the chemokine receptor CCR9, ameliorates inflammation in a T cell mediated mouse colitis model

Abstract

C-C chemokine receptor 9 (CCR9) is the homing receptor for C-C motif chemokine ligand 25 (CCL25), and contributes to the maintenance of mucosal immunity and pathogenesis of inflammatory bowel disease (IBD) through the recruitment of T cells into the gut mucosa. Recent reports suggest that the interaction of CCR9 and CCL25 in the large intestine correlate with disease severity of colonic IBD. MLN3126 is an orally available small molecular compound with potent and selective CCR9 antagonist activity. MLN3126 inhibited CCL25-induced calcium mobilization in human CCR9 transfected cells and CCL25-induced chemotaxis of mouse primary thymocytes in a dose-dependent manner. The potential effect of MLN3126 in an activated T cell transfer mouse colitis model was compared with that of an anti-tumor necrosis factor (TNF)-α antibody. CCL25 protein was detected in the colon of mucosal epithelial cells and CCR9⁺ CD4⁺ T cells were observed in the lamina propria of the colon of mice with colitis. Dietary administration of MLN3126 to the mice maintained sufficient concentration of the compound in the plasma and dose-dependently inhibited progression of colitis compared to the vehicle control group. Anti-TNF-α antibody, a surrogate for a standard of care for IBD treatment, was also efficacious in the colitis model. These results suggest that MLN3126 would be a promising orally available CCR9 antagonist to treat colonic IBD.

Keywords: CCL25; CCR9 antagonist; Colitis; MLN3126; Migration.