| 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)
藤岡 ひかる 独立行政法人国立病院機構長崎医療センター, 臨床研究センター, 形態研究部長 (00264226)
喜多 宏人 自治医科大学, 消化器内科学, 助手 (80294974)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2005: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2004: ¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2003: ¥8,500,000 (Direct Cost: ¥8,500,000)
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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 / PPARα / ミトコンドリア抗原 / 抗原特異的T細胞 / 予後予測因子 / ミトコンドリア抗体 / 自己反応性T細胞 / CD8陽性T細胞 / 病因関連抗原 |
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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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