Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells

• Published in: Biochemical and biophysical research communications 2017-04, Vol.485 (2), p.468-475
• Main Authors: Kawakami, Kentaro, Minami, Naoki, Matsuura, Minoru, Iida, Tomoya, Toyonaga, Takahiko, Nagaishi, Kanna, Arimura, Yoshiaki, Fujimiya, Mineko, Uede, Toshimitsu, Nakase, Hiroshi
• Format: Article
• Language: English
• Subjects: 60 APPLIED LIFE SCIENCES; Acute Disease; Allografts; Animals; APOPTOSIS; Apoptosis - genetics; Apoptosis - immunology; BONE MARROW CELLS; Bone Marrow Transplantation - adverse effects; Bone Marrow Transplantation - methods; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines - genetics; Cytokines - immunology; Cytokines - metabolism; Epithelial Cells - immunology; Fas Ligand Protein - genetics; Fas Ligand Protein - immunology; Fas Ligand Protein - metabolism; Flow Cytometry; Gastrointestinal Diseases - genetics; Gastrointestinal Diseases - immunology; Gastrointestinal Diseases - metabolism; Gene Expression - immunology; GEOGRAPHIC INFORMATION SYSTEMS; Graft versus-host disease (GVHD); Graft vs Host Disease - etiology; Graft vs Host Disease - genetics; Graft vs Host Disease - immunology; Intestinal Mucosa - immunology; Intestinal Mucosa - metabolism; Intestinal Mucosa - pathology; KNOCK-OUT REACTIONS; LARGE INTESTINE; Lymphocyte Count; MICE; Mice, Inbred C57BL; Mice, Inbred DBA; Mice, Knockout; Microscopy, Fluorescence; Osteopontin; Osteopontin - genetics; Osteopontin - immunology; Osteopontin - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Severity of Illness Index; SPLEEN CELLS; STEM CELLS
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2017.02.047

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. •A lack of osteopontin in donor cells exacerbated clinical gastrointestinal GVHD.•Donor cells lacking osteopontin affected intestinal inflammation of GVHD.•Donor cells lacking osteopontin increased apoptotic epithelial cells in GVHD.•Osteopontin plays an anti-inflammatory role in acute gastrointestinal GVHD.