title: Blockade of Syk ameliorates the development of murine sclerodermatous chronic graft-versus-host disease.
abstract: BACKGROUND
  Murine sclerodermatous chronic graft-versus-host disease (Scl-cGVHD) is a model for human Scl-cGVHD and systemic sclerosis (SSc). Syk is expressed in most of hematopoietic cells, fibroblasts, and endothelial cells. Syk is a protein tyrosine kinase that has an important role in transmitting signals from a variety of cell surface receptors.
  
  
  OBJECTIVE
  This study aims to investigate the effect of R788 (fostamatinib sodium), an oral prodrug that is rapidly converted to a potent inhibitor of Syk, R406, on Scl-cGVHD.
  
  
  METHODS
  R788 was orally administered twice a day to allogeneic recipients from day 14 to day 42 after bone marrow transplantation (BMT). In vitro, proliferation of GVHD-derived CD4(+) T cells and CD11b(+) cells was analyzed by R406.
  
  
  RESULTS
  Allogeneic BMT increased Syk phosphorylation in T, B, and CD11b(+) cells. The administration of R788 attenuated severity and fibrosis of Scl-cGVHD. The elevated expressions of CXCR4 on T cells, B cells, and CD11b(+) cells were significantly down-regulated by R788 treatment. R788 reduced memory CD4(+) T cells (CD44(hi)CD62L(-)CD4(+)). R406 inhibited proliferation of GVHD CD4(+) T cells and CD11b(+) cells in vitro. In addition, R788 treatment, inhibited proliferation of CD11b(+) cells in Scl-cGVHD mice. R788 treatment also reduced skin mRNA expressions of MCP-1, MIP-1α, IFN-γ, IL-13, IL-17A, and TGF-β1, but not influenced RANTES, CXCL12, and TFN-α.
  
  
  CONCLUSIONS
  Blockade of Syk suppressed migration factor of immune cells and antigen-specific memory CD4(+) T cells and proliferation and activation of GVHD CD4(+) T cells and CD11b(+) cells. The current studies suggested that Syk inhibitor is a potential candidate for use in treating patients with Scl-cGVHD and SSc.
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-8641, Japan; Department of Dermatology and Venereology, Hanoi Medical University, 1 Ton That Tung, Hanoi, Viet Nam.
authors.forename: Doanh
authors.initials: D
authors.lastname: Le Huu
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kimura
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Mutsumi
authors.initials: M
authors.lastname: Date
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Yasuhito
authors.initials: Y
authors.lastname: Hamaguchi
authors.affiliation: Department of Dermatology, University of Fukui, Fukui 910-1193, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Hasegawa
authors.affiliation: Department of Dermatology and Venereology, Hanoi Medical University, 1 Ton That Tung, Hanoi, Viet Nam.
authors.forename: Khang Tran
authors.initials: KT
authors.lastname: Hau
authors.affiliation: Department of Dermatology, Faculty of Medicine, University of Tsukuba, Tennodai, Tsukuba 305-8575, Japan. Electronic address: fujimoto-m@umin.ac.jp.
authors.forename: Manabu
authors.initials: M
authors.lastname: Fujimoto
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-8641, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Takehara
authors.affiliation: Department of Dermatology, Faculty of Medicine, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa 920-8641, Japan. Electronic address: t-matsushita@med.kanazawa-u.ac.jp.
authors.forename: Takashi
authors.initials: T
authors.lastname: Matsushita
mesh_terms: D000631:Aminopyridines; D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D016026:Bone Marrow Transplantation; D018925:Chemokines / Q000378:metabolism; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D005260:Female; D006086:Graft vs Host Disease / Q000188:drug therapy*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors*; D008297:Male; D008807:Mice, Inbred BALB C; D009000:Monocytes / Q000187:drug effects; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology / Q000627:therapeutic use*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors*; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011743:Pyrimidines; D019718:Receptors, CXCR4 / Q000378:metabolism; D012595:Scleroderma, Systemic / Q000188:drug therapy* / Q000276:immunology; D000072377:Syk Kinase; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism
chemical_list: D000631:Aminopyridines; C514936:CXCR4 protein, mouse; D018925:Chemokines; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D011725:Pyridines; D011743:Pyrimidines; D019718:Receptors, CXCR4; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; C523665:fostamatinib
keywords: CXCR4; Chronic GVHD; Memory T cells; Syk; Systemic sclerosis