Antibody blockade of CCL25/CCR9 ameliorates early but not late chronic murine ileitis.
OBJECTIVE
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 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.


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.
Rivera-Nieves
Jesús
J
Digestive Health Center of Excellence, Department of Internal Medicine, University of Virginia, Charlottesville, Virginia, USA. jr3u@virginia.edu
Ho
Johnson
J
Bamias
Giorgos
G
Ivashkina
Natalia
N
Ley
Klaus
K
Oppermann
Martin
M
Cominelli
Fabio
F
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D019742:Chemokines, CC / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology; D002908:Chronic Disease; D007079:Ileitis / Q000276:immunology / Q000628:therapy*; D016023:Integrins / Q000032:analysis; D015847:Interleukin-4 / Q000096:biosynthesis; D019041:L-Selectin / Q000032:analysis; D051379:Mice; D008806:Mice, Inbred AKR; D054388:Receptors, CCR; D019707:Receptors, Chemokine / Q000032:analysis / Q000037:antagonists & inhibitors* / Q000502:physiology
D000911:Antibodies, Monoclonal; C119309:CC chemokine receptor 9; C491541:Ccl25 protein, mouse; D019742:Chemokines, CC; D016023:Integrins; D054388:Receptors, CCR; D019707:Receptors, Chemokine; C070709:integrin alphaEbeta7; D019041:L-Selectin; D015847:Interleukin-4