title: A critical role for the retinoic acid signaling pathway in the pathophysiology of gastrointestinal graft-versus-host disease.
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.
authors.affiliation: Division of Hematology/Oncology, Medical College of Wisconsin, Milwaukee, WI 53226, USA. xchen@mcw.edu
authors.forename: Xiao
authors.initials: X
authors.lastname: Chen
authors.forename: Joseph
authors.initials: J
authors.lastname: Dodge
authors.forename: Richard
authors.initials: R
authors.lastname: Komorowski
authors.forename: William R
authors.initials: WR
authors.lastname: Drobyski
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects; D002478:Cells, Cultured; D003106:Colon / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005767:Gastrointestinal Diseases / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D006086:Graft vs Host Disease / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D008223:Lymphoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009928:Organ Specificity / Q000187:drug effects; D018168:Receptors, Retinoic Acid / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000072482:Retinoic Acid Receptor alpha; D012720:Severity of Illness Index; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D014212:Tretinoin / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*
chemical_list: C000607072:Rara protein, mouse; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014212:Tretinoin