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Inflamm Bowel Dis. 2011 Dec;17(12):2443-55. doi: 10.1002/ibd.21672. Epub 2011 Mar 4.

Granulocyte-macrophage colony stimulating factor blockade promotes ccr9(+) lymphocyte expansion in Nod2 deficient mice.

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1
Gastroenterology, Hepatology, and Nutrition, Children's Hospital Medical Center and the University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. charles.samson@cchmc.org

Abstract

BACKGROUND:

Ileal involvement in Crohn's disease (CD) is associated with NOD2 mutations and granulocyte-macrophage colony stimulating factor autoantibodies (GM-CSF Ab), and GM-CSF blockade promotes ileitis in Nod2/Card15-deficient (C15KO) mice. RALDH2-expressing dendritic cells (DC) and IL-4 promote CCR9 imprinting and small bowel homing of T lymphocytes, in conjunction with CCL25 expression by ileal epithelial cells (IEC). We hypothesized that GM-CSF neutralization promotes ileal disease by modulating expression of CCL25 by IEC and CCR9 by T lymphocytes via Nod2-dependent and independent pathways.

METHODS:

CCL25 and CCR9 expression were determined in pediatric CD patients stratified by GM-CSF Ab. Ileitis was induced in C15KO mice via GM-CSF Ab administration followed by nonsteroidal antiinflammatory drug (NSAID) exposure, and expression of CCL25, CCR9, FOXP3, intracellular cytokines, and RALDH2 was determined in IEC and immune cell populations.

RESULTS:

The frequency of CCL25(+) IEC and CCR9(+) T lymphocytes was increased in CD patients with elevated GM-CSF Ab. In the murine model, GM-CSF blockade alone induced IEC CCL25 expression, and reduced the frequency of mesenteric lymph node (MLN) CD4(+) FOXP3(+) cells, while Card15 deficiency alone enhanced MLN DC RALDH2 expression. Both GM-CSF neutralization and Card15 deficiency were required for downregulation of MLN DC IL-10 expression; under these conditions NSAID exposure led to an expansion of IL-4(+) and IL-17(+) CCR9(+) lymphocytes in the ileum.

CONCLUSIONS:

GM-CSF prevents ileal expansion of CCR9(+) lymphocytes via Nod2-dependent and independent pathways. CCR9 blockade may be beneficial in CD patients with elevated GM-CSF Ab.

PMID:
21381154
PMCID:
PMC3111853
DOI:
10.1002/ibd.21672
[Indexed for MEDLINE]
Free PMC Article

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