2005 Fiscal Year Final Research Report Summary
Dissection of autoimmune response and establishment of diagnosis and treatment of primary biliary cirrhosis
| Project/Area Number |
15390238
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Clinical Research Center National Hospital Organization (NHO) Nagasaki Medical Center |
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Principal Investigator |
ISHIBASHI Hiromi Clinical Research Center, Nagasaki Medical Center, 臨床研究センター, 臨床研究センター長 (80127969)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAMURA Minoru Clinical Research Center, Nagasaki Medical Center, 臨床研究センター, 先端技術研究部長 (40217906)
MIGITA Kiyoshi Clinical Research Center, Nagasaki Medical Center, 臨床研究センター, 病因解析研究部長 (60264214)
KOMORI Atsumasa Clinical Research Center, Nagasaki Medical Center, 臨床研究センター, 再生医療研究部長 (50234901)
ITO Masahiro Clinical Research Center, Nagasaki Medical Center, 臨床研究センター, 部長 (30184691)
SHIMODA Shinji Kyushu University Graduate School of Medical Science, Medicine and Biosystemic Science, 大学院・病態修復内科学, 助手 (30279319)
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| Project Period (FY) |
2003 – 2005
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| Keywords | primary biliary cirrhosis / bile duct damage / biliary epithelial cells / innate immunity / Toll-like receptor (TLR) / anti-gp210 antibody / prediction of prognosis / anti-mitochondrial antibody |
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| Research Abstract |
The objective of this study is to dissect the mechanism of autoimmune response in primary biliary cirrhosis (PBC) in order to develop the new strategy for the treatment of PBC.
Fist, we established human T cell clones derived from PBC patients or healthy subjects which react to PDC-E2/OGDC-E2 peptides. Using these T cell clones, we found that T cells reactive to PDC-E2 peptide cross-react to peptides derived from nuclear pore antigens (gp210), supporting the hypothesis that molecular mimicry is operative in the development of PBC. We also found that T cells derived from PBC patients are costimulation-independent, while T cells derived from health subjects are costimulation-dependent. The costimulation-independent autoreactive T cells, which do not become anergic when they contact with biliary epithelial cells (BEC), might play the pathological role in the development of PBC.
Second, we studied the role of BEC in the regulation of autoimmune response using T cell clones reactive to PDC-E2
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peptides and human biliary epithelial cells (HIBEC) in vitro. We found that HIBEC can strongly inhibit the function of autoreactive T cells by producing prostaglandin-E2. We also found that Toll-like receptors (TLRs) 2,3,4 and 9 are constitutively expressed in HIBEC and the stimulation of these TLRs by their ligands induced the secretion of IL-6, IL-8 and MCP-1 via NF-kB and MAPK pathway. The expression of TLR4 was increased on the biliary epithelial cells of interlobular bile ducts in PBC liver. TLR3-type I interferon pathway was also activated in PBC liver. These results indicate that innate immune response may play a role in the initiation and/or maintenance of autoimmune response in PBC.
Finally, we studied the serological markers that can predict the long-term outcome of PBC patients. We found that patients who are sustained positive for anti-gp210 antibodies are at high risk for the progression to end-stage hepatic failure. Although the mechanism of the production of anti-gp210 antibodies remains to be elucidated, this predictive autoantibody should be useful for the identification of PBC patients who require treatment and long-term follow-up. Less
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[Journal Article] Human intrahepatic biliary epithelial cells function in innate immunity by producing IL-6 and IL-8 via the TLR4-NF-kappaB and -MAPK signaling pathways.2006
Author(s)
Yokoyama T, Komori A, Nakamura M, Takii Y, Kamihira T, Shimoda S, Mori T, Fujiwara S, Koyabu M, Taniguchi K, Fujioka H, Migita K, Yatsuhashi H, Ishibashi H
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Journal Title
Liver Int. 26(4)
Pages: 467-476
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Increased expression of nuclear envelope gp210 antigen in small bile ducts in primary biliary cirrhosis.2006
Author(s)
Nakamura M, Takii Y, Ito M, Komori A, Yokoyama T, Shimizu-Yoshida Y, Koyabu M, Matsuyama M, Mori T, Kamihira T, Daikoku M, Migita K, Yatsuhashi H, Nozaki N, Shimoda S, Ishibashi H
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Journal Title
J.Autoimmunity 26(2)
Pages: 138-145
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Immunosuppressant FK506 inhibits matrix metalloproteinase-9 induction in TNF-alpha-stimulated human hepatic stellate cells.2006
Author(s)
Migita K, Maeda Y, Abiru S, Nakamura M, Komori A, Yokoyama T, Takii Y, Mori T, Yatsuhashi H, Eguchi K, Ishibashi H
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Journal Title
Life Sci. 78(21)
Pages: 2510-2515
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Antibody titer to gp210-C terminal peptide as a clinical parameter for monitoring primary biliary cirrhosis.2005
Author(s)
Nakamura M, Shimizu-Yoshida Y, Takii Y, Komori A, Yokoyama T, Ueki T, Daikoku M, Yano K, Matsumoto T, Migita K, Yatsuhashi H, Ito M, Masaki N, Adachi H, Watanabe Y, Nakamura Y, Saoshiro T, Sodeyama T, Koga M, Shimoda S, Ishibashi H
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Journal Title
J.Hepatol. 42(3)
Pages: 386-392
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Enhanced expression of type I interferon and toll-like receptor-3 in primary biliary cirrhosis.2005
Author(s)
Takii Y, Nakamura M, Ito M, Yokoyama T, Komori A, Shimizu-Yoshida Y, Nakao R, Kusumoto K, Nagaoka S, Yano K, Abiru S, Ueki T, Matsumoto T, Daikoku M, Taniguchi K, Fujioka H, Migita K, Yatsuhashi H, Nakashima M, Harada M, Ishibashi H
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Journal Title
Lab Invest. 85(7)
Pages: 908-920
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Lipopolysaccharide signaling induces serum amyloid A (SAA) synthesis in human hepatocytes in vitro.2004
Author(s)
Migita K, Abiru S, Nakamura M, Komori A, Yoshida Y, Yokoyama T, Daikoku M, Ueki T, Takii Y, Yano K, Yatsuhashi H, Eguchi K, Ishibashi H.
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Journal Title
FEBS Let. 569(1-3)
Pages: 235-239
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Distinct costimulation dependent and independent autoreactive T-cell clones in primary biliary cirrhosis.2003
Author(s)
Kamihira T, Shimoda S, Harada K, Kawano A, Handa M, Baba E, Tsuneyama K, Nakamura M, Ishibashi H, Nakanuma Y, Gershwin ME, Harada M.
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Journal Title
Gastroenterology 125(5)
Pages: 1379-1387
Description
「研究成果報告書概要(欧文)」より
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[Book] 肝臓病の最新治療(戸田剛太郎,沖田極,門田守人,井廻道夫,幕内雅敏,恩地森一,森正樹,茶山一彰,持田智,銭谷幹男編集)2006
Author(s)
石橋大海, 下田慎治, 中村稔
Total Pages
406
Publisher
先端医療技術研究所
Description
「研究成果報告書概要(和文)」より
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