title: Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells.
abstract: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD.
  
  
  
  OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses.
  
  
  
  The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group.
  
  
  
  We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway.
authors.affiliation: Department of Gastroenterology and Hepatology, Sapporo Medical University, School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Kawakami
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University, Graduate School of Medicine, 54 Shogoin, Kawahara-Cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Minami
authors.affiliation: Department of Gastroenterology and Hepatology, Kyoto University, Graduate School of Medicine, 54 Shogoin, Kawahara-Cho, Sakyo-ku, Kyoto 606-8507, Japan.
authors.forename: Minoru
authors.initials: M
authors.lastname: Matsuura
authors.affiliation: Department of Gastroenterology and Hepatology, Sapporo Medical University, School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan.
authors.forename: Tomoya
authors.initials: T
authors.lastname: Iida
authors.affiliation: Center for Advanced IBD Research and Treatment, Kitasato University Kitasato Institute Hospital, 5-9-1, Shirokane, Minato-ku, Tokyo 108-8642, Japan.
authors.forename: Takahiko
authors.initials: T
authors.lastname: Toyonaga
authors.affiliation: Department of Anatomy, Sapporo Medical University, School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan.
authors.forename: Kanna
authors.initials: K
authors.lastname: Nagaishi
authors.affiliation: Department of Gastroenterology and Hepatology, Sapporo Medical University, School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Arimura
authors.affiliation: Department of Anatomy, Sapporo Medical University, School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan.
authors.forename: Mineko
authors.initials: M
authors.lastname: Fujimiya
authors.affiliation: Department of Matrix Medicine, Institute for Genetic Medicine, Hokkaido University, Sapporo Kita 15-jo Nishi 7-chome, Kita-ku, Sapporo, Hokkaido 060-0815, Japan.
authors.forename: Toshimitsu
authors.initials: T
authors.lastname: Uede
authors.affiliation: Department of Gastroenterology and Hepatology, Sapporo Medical University, School of Medicine, Minami 1-jo Nishi 17-chome, Chuo-ku, Sapporo, Hokkaido 060-8556, Japan. Electronic address: hiropynakase@gmail.com.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nakase
mesh_terms: D000208:Acute Disease; D064591:Allografts; D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000379:methods; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016207:Cytokines / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D004847:Epithelial Cells / Q000276:immunology*; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D005767:Gastrointestinal Diseases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015870:Gene Expression / Q000276:immunology; D006086:Graft vs Host Disease / Q000209:etiology / Q000235:genetics / Q000276:immunology*; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018655:Lymphocyte Count; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D053495:Osteopontin / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012720:Severity of Illness Index
chemical_list: D016207:Cytokines; D053222:Fas Ligand Protein; D053495:Osteopontin
keywords: Apoptosis; Graft versus-host disease (GVHD); Osteopontin