Abstract
Purpose: CCL25 mediates the homeostatic trafficking of CCR9-expressing lymphocytes to the small intestine, but the function of this chemokine/receptor pair during chronic small intestinal inflammation has yet to be determined. Furthermore, although clinical trials to evaluate the efficacy of targeting the CCL25/CCR9 axis for the treatment of Crohn's disease are being conducted, preclinical data in animal models of IBD are lacking. The purpose of this study was to provide preclinical data for the potential efficacy of this anti-chemokine strategy in a clinically relevant spontaneous mouse model of Crohn's disease. Methods: In the current studies we investigate the expression of CCL25 and CCR9 as a function of disease progression in a spontaneous murine model of chronic ileitis (SAMP1/YitFc), using flow cytometry, real time RT-PCR, ELISA and immunohistochemistry. In addition, we assess the functional role of the axis in the overall disease process through therapeutic studies that target the chemokine or the receptor, during early and late disease. Results: The percentage of CCR9-expressing lymphocytes increased during early disease, accompanied by the appearance of a population of CCR9high lymphocytes, predominantly within CD8+ T cells. Yet different from patients with primary sclerosing cholangitis, the expression of CCL25 remained restricted to the small intestine, even in mice with bile duct inflammation. Neutralization of the receptor or the chemokine attenuated early disease, but showed no therapeutic efficacy during the later stages, when overall CCR9 expression decreased and the CCR9high population was absent. Conclusions: Our studies demonstrate that the role of this chemokine axis is not limited to homeostatic recruitment, as previously believed. However these molecules appear to play their most crucial role during the early stages of chronic murine ileitis. Our data suggests that careful selection of patients in whom the disease involves the small intestine and who have elevated levels of CCR9-expressing cells may enhance the response rate of subsequent clinical studies that aim at this chemokine/receptor pair for the treatment of small intestinal Crohn's disease.
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