title: FTY720 ameliorates murine sclerodermatous chronic graft-versus-host disease by promoting expansion of splenic regulatory cells and inhibiting immune cell infiltration into skin.
abstract: OBJECTIVE
  Sphingosine 1-phosphate (S1P) exerts a variety of activities in immune, inflammatory, and vascular systems. S1P plays an important role in systemic sclerosis (SSc) pathogenesis. Regulation of S1P in fibrotic diseases as well as in SSc was recently reported. FTY720, an oral S1P receptor modulator, has been shown to be a useful agent for the prevention of transplant rejection and autoimmune diseases. Murine sclerodermatous chronic graft-versus-host disease (GVHD) is a model for human sclerodermatous chronic GVHD and SSc. We undertook this study to investigate the effects of FTY720 in murine sclerodermatous chronic GVHD.
  
  
  METHODS
  FTY720 was orally administered to allogeneic recipient mice from day 0 to day 20 (short-term, early-treatment group), from day 0 to day 42 (full-term, early-treatment group), or from day 22 to day 42 (delayed-treatment group) after bone marrow transplantation.
  
  
  RESULTS
  Delayed administration of FTY720 attenuated, and early administration of FTY720 inhibited, the severity and fibrosis in murine sclerodermatous chronic GVHD. With early treatment, FTY720 induced expansion of splenic myeloid-derived suppressor cells, Treg cells, and Breg cells. Vascular damage in chronic GVHD was inhibited by FTY720 through down-regulating serum levels of S1P and soluble E-selectin. FTY720 inhibited infiltration of immune cells into skin. Moreover, FTY720 diminished the expression of messenger RNA for monocyte chemotactic protein 1, macrophage inflammatory protein 1α, RANTES, tumor necrosis factor α, interferon-γ, interleukin-6 (IL-6), IL-10, IL-17A, and transforming growth factor β1 in the skin.
  
  
  CONCLUSIONS
  FTY720 suppressed the immune response by promoting the expansion of regulatory cells and reducing vascular damage and infiltration of immune cells into the skin. Taken together, these results have important implications for the potential use of FTY720 in the treatment of sclerodermatous chronic GVHD and SSc in humans.
authors.affiliation: Kanazawa University, Kanazawa, Japan.
authors.forename: Doanh Le
authors.initials: DL
authors.lastname: Huu
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
authors.forename: Guihua
authors.initials: G
authors.lastname: Jin
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Hamaguchi
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D000068876:Fingolimod Hydrochloride; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D011409:Propylene Glycols / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012594:Scleroderma, Localized / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D012867:Skin / Q000276:immunology* / Q000473:pathology; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013154:Spleen / Q000276:immunology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D051059:PTEN Phosphohydrolase; C487757:Pten protein, mouse; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine