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Blood. 2013 May 9;121(19):3970-80. doi: 10.1182/blood-2012-08-445130. Epub 2013 Mar 25.

A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease.

Author information

1
Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. xchen@mcw.edu

Abstract

Damage to the gastrointestinal tract during graft-versus-host disease (GVHD) is one of the major causes of morbidity and mortality in allogeneic hematopoietic stem cell transplant (HSCT) recipients. In the current study, we identified a critical role for the retinoic acid (RA) signaling pathway in the induction and propagation of gastrointestinal GVHD. The administration of exogenous RA significantly increased expression of the gut-homing molecules, CCR9 and α4β7, on donor T cells in mesenteric lymph nodes, and augmented the accumulation of proinflammatory CD4(+) and CD8(+) T cells within the gut mucosa, leading to a selective exacerbation of colonic GVHD and increased overall mortality. Conversely, depletion of RA in recipient mice by vitamin A deprivation resulted in a dramatic reduction of gut-homing molecule expression on donor T cells after HSCT. Significantly, absence of the RA receptor-α on donor T cells markedly attenuated the ability of these cells to cause lethal GVHD. This observation was attributable to a significant reduction in pathological damage within the colon. These findings identify an organ-specific role for RA in GVHD and provide evidence that blockade of the RA signaling pathway may represent a novel strategy for mitigating the severity of colonic GVHD.

PMID:
23529927
PMCID:
PMC3650708
DOI:
10.1182/blood-2012-08-445130
[Indexed for MEDLINE]
Free PMC Article

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