title: Halofugine prevents cutaneous graft versus host disease by suppression of Th17 differentiation.
abstract: Halofuginone, isolated from Dichroa febreifuga, is a potent inhibitor of skin collagen in chronic graft-versus-host disease (GVHD). To evaluate the effect of halofuginone on the development of cutaneous GVHD, we developed a murine model based on BALB/c (H-2d) as recipients with  transplantation of C57BL/6(H-2b) bone marrow plus splenocytes. Halofuginone or its vehicle dimethyl sulfoxide (DMSO) was given introperitoneally at a dose of 5 ug/mouse daily from one day before transplantation until 20 days post-transplantation. Halofuginone-treated recipients showed  only very mild appearance of cutaneous GVHD, whereas DMSO-treated recipients rapidly showed manifestation of severe cutaneous GVHD, indicating a protective effect of halofuginone in cutaneous GVHD. After injected with halofuginone, we observed a decrease in the number of CD4(+) interleukin  (IL)-17(+) cells and a parallel increase in that of CD4(+) interferon (IFN)-gamma(+) cells in peripheral blood. This shift between CD4(+) IL-17(+) cells and CD4(+) IFN-gamma(+) cells developed through modulation of cytokine profile  indicated by a marked increase in the levels of IFN-gamma, tumor necrosis factor (TNF)-alpha, and IL-6. The level of IL-10 was not changed obviously. Mechanistically, we demonstrate that severe tissue damage was associated with the production of IL-17 and expansion of CD4(+)IL-17(+)  cells during this disorder. Specific inhibition of Th17 differentiation by halofuginone reduced disease severity. Our results indicate a significant role of halofuginone in suppressing cutaneous GVHD, apparently through effect on inhibition of Th17 cells differentiation.
authors.affiliation: The Affiliated Hospital of Xuzhou Medical College, Xuzhou, China.
authors.forename: Hai
authors.initials: H
authors.lastname: Cheng
authors.forename: Jing
authors.initials: J
authors.lastname: Tian
authors.forename: Lingyu
authors.initials: L
authors.lastname: Zeng
authors.forename: Bin
authors.initials: B
authors.lastname: Pan
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Li
authors.forename: Guoliang
authors.initials: G
authors.lastname: Song
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Kailin
authors.initials: K
authors.lastname: Xu
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D016026:Bone Marrow Transplantation; D002454:Cell Differentiation / Q000187:drug effects* / Q000276:immunology; D002908:Chronic Disease; D016207:Cytokines / Q000276:immunology; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010880:Piperidines / Q000494:pharmacology*; D052999:Quinazolinones / Q000494:pharmacology*; D012871:Skin Diseases / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D058504:Th17 Cells / Q000276:immunology* / Q000473:pathology; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D020533:Angiogenesis Inhibitors; D016207:Cytokines; D010880:Piperidines; D052999:Quinazolinones; C010176:halofuginone