Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease. Blood 2009 Mar 05;113(10):2352-62
Date
12/09/2008Pubmed ID
19059877Pubmed Central ID
PMC2652376DOI
10.1182/blood-2008-08-175448Scopus ID
2-s2.0-63849105635 (requires institutional sign-in at Scopus site) 67 CitationsAbstract
Damage to the gastrointestinal tract during graft-versus-host disease (GVHD) from the conditioning regimen in conjunction with alloreactive donor T cells plays a pivotal role in the pathogenesis of this disease. In this study, we have identified secretion of interleukin-23 (IL-23) by donor antigen-presenting cells (APCs) as a critical event in the induction of GVHD of the colon linking conditioning regimen-induced mucosal injury and lipopolysaccharide (LPS) translocation to subsequent proinflammatory cytokine production and GVHD-associated pathologic damage. In the absence of donor APC-derived IL-23 secretion, there is a selective and profound reduction in pathologic damage as well as a marked reduction in LPS and proinflammatory cytokine production in the colon microenvironment. The downstream proinflammatory effects of IL-23 are dependent upon donor-derived secretion of interferon-gamma (IFN-gamma), but are independent of donor IL-17 production. These findings define a novel organ-specific role for IL-23 in the pathophysiology of GVHD and demonstrate that IL-23 can direct tissue-specific pathology within the context of a systemic inflammatory disorder. Furthermore, these studies also identify IL-23 as a potential therapeutic target for the prevention of this life-threatening disorder.
Author List
Das R, Chen X, Komorowski R, Hessner MJ, Drobyski WRAuthors
Xiao Chen MD, PhD Associate Professor in the Medicine department at Medical College of WisconsinWilliam R. Drobyski MD Professor in the Medicine department at Medical College of Wisconsin
Martin J. Hessner PhD Professor in the Pediatrics department at Medical College of Wisconsin
MESH terms used to index this publication - Major topics in bold
AnimalsAntigen-Presenting Cells
Bone Marrow Transplantation
Colon
Cytokines
Flow Cytometry
Gene Expression
Graft vs Host Disease
Interleukin-23
Lipopolysaccharides
Mice
Receptors, Interleukin
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction
Transplantation Conditioning