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Mucosal Immunol. 2016 Mar;9(2):309-21. doi: 10.1038/mi.2015.61. Epub 2015 Jul 8.

Donor interleukin-22 and host type I interferon signaling pathway participate in intestinal graft-versus-host disease via STAT1 activation and CXCL10.

Lamarthée B1,2,3, Malard F4,5,6, Gamonet C1,2,3, Bossard C7,8, Couturier M1,2,3, Renauld JC9, Mohty M4,5,6, Saas P1,2,3, Gaugler B1,2,3.

Author information

INSERM UMR1098, Besançon, France.
Université de Bourgogne Franche-Comté, UMR 1098, SFR FED 4234, Besançon, France.
EFS Bourgogne Franche-Comté, UMR 1098, Besançon, France.
Centre de Recherche Saint-Antoine, INSERM UMRs938, Paris, France.
Université Pierre et Marie Curie, Paris, France.
Service d'Hématologie Clinique, Hôpital Saint-Antoine, Paris, France.
EA4273 Biometadys, Faculté de médecine, Université de Nantes, Nantes, France.
Service d'Anatomie et Cytologie Pathologique, CHU de Nantes, Nantes, France.
Ludwig Institute for Cancer Research and Experimental Medicine Unit, Université Catholique de Louvain, Brussels, Belgium.


Acute graft-versus-host disease (aGVHD) remains a major complication following allogeneic hematopoietic cell transplantation, limiting the success of this therapy. We previously reported that interleukin-22 (IL-22) participates to aGVHD development, but the underlying mechanisms of its contribution remain poorly understood. In this study, we analyzed the mechanism of the pathological function of IL-22 in intestinal aGVHD. Ex-vivo colon culture experiments indicated that IL-22 was able to induce Th1-like inflammation via signal transducer and activator of transcription factor-1 (STAT1) and CXCL10 induction in the presence of type I interferon (IFN). To evaluate a potential synergy between IL-22 and type I IFN in aGVHD, we transplanted recipient mice, either wild-type (WT) or type I IFN receptor deficient (IFNAR(-/-)), with bone marrow cells and WT or IL-22 deficient (IL-22(-/-)) T cells. We observed a decreased GVHD severity in IFNAR(-/-) recipient of IL-22(-/-) T cells, which was associated with a lower level of STAT1 activation and reduced CXCL10 expression in the large intestine. Finally, immunohistochemistry staining of STAT1 performed on gastrointestinal biopsies of 20 transplanted patients showed exacerbated STAT1 activation in gastrointestinal tissues of patients with aGVHD as compared with those without aGVHD. Thus, interfering with both IL-22 and type I IFN signaling may provide a novel approach to limit aGVHD.

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