title: Synthetic retinoid Am80 ameliorates chronic graft-versus-host disease by down-regulating Th1 and Th17.
abstract: Chronic GVHD (cGVHD) is a main cause of late death and morbidity after allogeneic hematopoietic cell transplantation, but its pathogenesis remains unclear. We investigated the roles of Th subsets in cGVHD with the use of a well-defined mouse model of cGVHD. In this model, development of cGVHD was associated with up-regulated Th1, Th2, and Th17 responses. Th1 and Th2 responses were up-regulated early after BM transplantation, followed by a subsequent up-regulation of Th17 cells. Significantly greater numbers of Th17 cells were infiltrated in the lung and liver from allogeneic recipients than those from syngeneic recipients. We then evaluated the roles of Th1 and Th17 in cGVHD with the use of IFN-γ-deficient and IL-17-deficient mice as donors. Infusion of IFN-γ(-/-) or IL-17(-/-) T cells attenuated cGVHD in the skin and salivary glands. Am80, a potent synthetic retinoid, regulated both Th1 and Th17 responses as well as TGF-β expression in the skin, resulting in an attenuation of cutaneous cGVHD. These results suggest that Th1 and Th17 contribute to the development of cGVHD and that targeting Th1 and Th17 may therefore represent a promising therapeutic strategy for preventing and treating cGVHD.
authors.affiliation: Department of Hematology and Oncology, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan;
authors.forename: Hisakazu
authors.initials: H
authors.lastname: Nishimori
authors.forename: Yoshinobu
authors.initials: Y
authors.lastname: Maeda
authors.forename: Takanori
authors.initials: T
authors.lastname: Teshima
authors.forename: Haruko
authors.initials: H
authors.lastname: Sugiyama
authors.forename: Koichiro
authors.initials: K
authors.lastname: Kobayashi
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Yamasuji
authors.forename: Sachiyo
authors.initials: S
authors.lastname: Kadohisa
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Uryu
authors.forename: Kengo
authors.initials: K
authors.lastname: Takeuchi
authors.forename: Takehiro
authors.initials: T
authors.lastname: Tanaka
authors.forename: Tadashi
authors.initials: T
authors.lastname: Yoshino
authors.forename: Yoichiro
authors.initials: Y
authors.lastname: Iwakura
authors.forename: Mitsune
authors.initials: M
authors.lastname: Tanimoto
mesh_terms: D000818:Animals; D001565:Benzoates / Q000627:therapeutic use*; D016026:Bone Marrow Transplantation; D016207:Cytokines / Q000378:metabolism; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000517:prevention & control*; D007371:Interferon-gamma / Q000502:physiology; D020381:Interleukin-17 / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D012176:Retinoids / Q000627:therapeutic use*; D015996:Survival Rate; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D058504:Th17 Cells / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014184:Transplantation, Homologous
chemical_list: D001565:Benzoates; D016207:Cytokines; D020381:Interleukin-17; D012333:RNA, Messenger; D012176:Retinoids; D013764:Tetrahydronaphthalenes; D016212:Transforming Growth Factor beta; C061133:tamibarotene; D007371:Interferon-gamma