Antibody Blockade of CCL25/CCR9 Ameliorates Early but not Late Chronic Murine Ileitis

Digestive Health Center of Excellence, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia, USA.
Gastroenterology (Impact Factor: 16.72). 12/2006; 131(5):1518-29. DOI: 10.1053/j.gastro.2006.08.031
Source: PubMed


CCL25 mediates the homeostatic recruitment 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.
In the current studies, we investigated 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 reverse-transcription polymerase chain reaction, enzyme-linked immunosorbent assay, and immunohistochemistry. In addition, we assessed 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.
The percentage of CCR9-expressing lymphocytes increased during early disease, accompanied by the appearance of a population of CCR9(high) 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 inflammation of the biliary tree. 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 CCR9(high) population was absent.
Our studies show 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.

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    • "However, accumulating evidences showed that the CCR9/ CCL25 axis participated in a variety of disease processes (Johnson-Holiday et al. 2011; Nakamoto et al. 2012; Schmutz et al. 2010). In Crohn's disease patients (M et al. 2007) and in a murine model (Apostolaki et al. 2008; Rivera-Nieves et al. 2006), CCL25 was up-regulated following accumulation of CCR9 ? CD4 ? "
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    • "Another example is CCR9, expressed on intraepithelial and lamina propria T cells. CCR9 is involved in intestinal infiltration in IBD [45], probably by responding to CCL25, expressed by epithelial cells, specifically in the small intestine [46]. Results from a phase II clinical trial using a CCR9 antagonist in CD patients resulted in reduced disease severity [47]. "
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    • "The ligand of this chemokine receptor, CCL25, is abundant in the SI but not the colon [5]. Furthermore, up-regulation of CCL25 in the inflamed SI following accumulation of CCR9 + CD4 + T cells has been reported in CD [6] and in a murine model [7]. Clinical trials involving an anti-CCR9 antagonist against CD are ongoing. "
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