Gastroenterology

Gastroenterology

Volume 131, Issue 5, November 2006, Pages 1518-1529
Gastroenterology

Basic–alimentary tract
Antibody Blockade of CCL25/CCR9 Ameliorates Early but not Late Chronic Murine Ileitis

https://doi.org/10.1053/j.gastro.2006.08.031Get rights and content

Background & Aims: 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. Methods: 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. 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 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 CCR9high population was absent. Conclusions: 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.

Section snippets

Mice

The SAMP1/YitFc substrain was generated after more than 30 generations of continuous inbreeding from 2 breeding pairs of SAMP1/Yit mice provided by Dr S. Matsumoto (Yakult Institute for Microbiological Research, Tokyo, Japan). Mice were kept under specific pathogen-free conditions at the University of Virginia.15 Because most identifiable genes were AKR derived, age-matched AKR/J mice were used as controls.16 Fecal samples from SAMP1/YitFc mice were consistently negative for Helicobacter

CCR9 Expression Is Increased in SAMP1/YitFc Mice During Disease Induction

We examined the surface expression of CCR9 on CD4+ and CD8+ cells isolated from the spleen and MLN of SAMP1/YitFc mice and compared it with that of noninflamed AKR control mice at 4–6 weeks of age. Phycoerythrin-labeled isotype antibody (mean fluorescence index [MFI] < 101, not shown) and lymphocytes isolated from the respective organs of CCR9-deficient mice were used as controls (Figure 1, dashed lines). CCR9+ T cells were identified in MLN and spleen of both control AKR and SAMP1YitFc mice (

Discussion

We investigated whether CCL25/CCR9 play a role in chronic inflammatory trafficking to the small intestine using the SAMP1/YitFc model of chronic ileitis.15, 26 This strain differs from other animal models of inflammatory bowel disease, because the site of inflammation coincides with the restricted location of CCL25 expression.31 We showed that the levels of CCL25 increased in inflamed small intestine compared with noninflamed mice and that further increases occur as the inflammation progresses.

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    Supported by US Public Health Service/National Institutes of Health grants DK067254 and DK057880, by a Harold Amos MMFDP grant from the Robert Wood Johnson Foundation (to J.R-N.), by Deutsche Forschungsgemeinschaft grants SFB402/B7 (to M.O.) and GRK335 to (N.I.), and by the Administrative, Morphology, and Immunology Cores of the University of Virginia Digestive Health Research Center (DK 56703).

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