Interleukin-23 secretion by donor antigen-presenting cells is critical for organ-specific pathology in graft-versus-host disease.
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.
Das
Rupali
R
Bone Marrow Transplant Program, Medical College of Wisconsin, Milwaukee, WI 53226, USA.
Chen
Xiao
X
Komorowski
Richard
R
Hessner
Martin J
MJ
Drobyski
William R
WR
D000818:Animals; D000938:Antigen-Presenting Cells / Q000378:metabolism*; D016026:Bone Marrow Transplantation / Q000009:adverse effects* / Q000276:immunology; D003106:Colon / Q000276:immunology* / Q000473:pathology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D005434:Flow Cytometry; D015870:Gene Expression; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D053759:Interleukin-23 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018123:Receptors, Interleukin / Q000096:biosynthesis / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D019172:Transplantation Conditioning / Q000009:adverse effects*
D016207:Cytokines; D053759:Interleukin-23; D008070:Lipopolysaccharides; D018123:Receptors, Interleukin; C528688:interleukin-23 receptor, mouse