2012 Fiscal Year Final Research Report
The mechanism of bile duct destruction in Primary Biliary Cirrhosis
| Project/Area Number |
22590739
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 | Kyushu University |
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Principal Investigator |
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| Project Period (FY) |
2010 – 2012
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| Keywords | 原発生胆汁性肝硬変 / 自然免疫 / モデルマウス |
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| Research Abstract |
Primary biliary cirrhosis (PBC) is characterized by chronic nonsuppurative destructive cholangitis (CNSDC) associated with destruction of small bile ducts. We examined the role of Toll-like receptors (TLRs), their ligands, and natural killer (NK) cells in modulating cytotoxic activity against biliary epithelial cells (BECs). We demonstrate that Toll-like receptor 4 ligand (TLR4-L)-stimulated NK cells destroy autologous BECs in the presence of interferon alpha (IFN-α) synthesized by TLR 3 ligand (TLR3-L)-stimulated monocytes (Mo). Indeed, IFN-α production by hepatic Mo is significantly increased in patients with PBC compared to disease controls. These data are supported by the immunohistochemical observation of an increased presence of CD56-positive NK cells scattered around destroyed small bile ducts more frequently in liver tissues from PBC patients than controls. To clarify the role of innate immune effector cells, such as natural killer (NK) cells, was studied in the mouse model based on the hypothesis that early events during immunization play an important role in the breakdown of tolerance. Following in-vivo depletion of NK cells, there is a marked suppression of anti-mitochondrial autoantibodies and cytokine production from autoreactive T cells. However, there was no change in the clinical pathology of portal inflammation compared to controls. These data support the hypothesis that there are probably multiple steps in the natural history of PBC, including a role of NK cells in initiating the breakdown of tolerance.
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[Journal Article] Epigenetic investigation of variably X chromosome inactivated genes in monozygotic female twins discordant for primary biliary cirrhosis2011
Author(s)
Mitchell MM, Lleo A, Zammataro L, Mayo MJ, Invernizzi P, Bach N, Shimoda S, Gordon S, Podda M, Gershwin ME, Selmi C, LaSalle JM
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Journal Title
Epigenetics
Volume: 6(1)
Pages: 95-102
Peer Reviewed
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[Journal Article] Significance of periductal Langerhans cells and biliary epithelial cell-derived macrophage inflammatory protein-3a in the pathogenesis of primary biliary cirrhosis2011
Author(s)
Harada K, Shimoda S, Ikeda H, Chiba M, Hsu M, Sato Y, Kobayashi M, Ren XS, Ohta H, Kasashima S, Kawashima A, Nakanuma Y
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Journal Title
Liver Int
Volume: 31(2)
Pages: 245-53
Peer Reviewed
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[Journal Article] Interaction between Toll-like receptors and natural killer cells in the destruction of bile ducts in primary biliary cirrhosis2011
Author(s)
Shimoda S, Harada K, Niiro H, Shirabe K, Taketomi A, Maehara Y, Tsuneyama K, Nakanuma Y, Leung P, Ansari AA, Gershwin ME, Akashi K
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Journal Title
Hepatology
Volume: 53(4)
Pages: 1270-81
Peer Reviewed
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[Journal Article] Modulation of CD4 T cell responses following splenectomy in hepatitis C virus-related liver cirrhosis2011
Author(s)
Hashimoto N, Shimoda S, Kawanaka H, Tsuneyama K, Uehara H, Akahoshi T, Kinjo N, Taketomi A, Shirabe K, Akashi K, Lleo A, Ansari AA, Gershwin ME, Maehara Y
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Journal Title
Clin Exp Immunol
Volume: 165(2)
Pages: 243-50
Peer Reviewed
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[Journal Article] Fine phenotypic and functional characterization of effector cluster of differentiation 8 positive T cells in human patients with primary biliary cirrhosis2011
Author(s)
Tsuda M, Ambrosini YM, Zhang W, Yang GX, Ando Y, Rong G, Tsuneyama K, Sumida K, Shimoda S, Bowlus CL, Leung PS, He XS, Coppel RL, Ansari AA, Lian ZX, Gershwin ME
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Journal Title
Hepatology
Volume: 54(4)
Pages: 1293-302
Peer Reviewed
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[Journal Article] Serum BAFF and APRIL levels in patients with PBC2010
Author(s)
Migita K, Ilyassova B, Kovzel EF, Nersesov A, Abiru S, Maeda Y, Komori A, Ito M, Yano K, Yatsuhashi H, Shimoda S, Ishibashi H, Nakamura M
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Journal Title
Clin Immunol.Feb
Volume: 134(2)
Pages: 217-25
Peer Reviewed
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[Journal Article] a signpost for biliary inflammation in primary biliary cirrhosis2010
Author(s)
Shimoda S, Harada K, Niiro H, Taketomi A, Maehara Y, Tsuneyama K, Kikuchi K, Nakanuma Y, Mackay IR, Gershwin ME, Akashi K CX3CL1 (fractalkine)
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Journal Title
Hepatology. Feb
Volume: 51(2)
Pages: 567-75
Peer Reviewed
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[Journal Article] Analysis of HLA-DRB1 polymorphisms in Japanese patients with primary biliary cirrhosis (PBC) The HLA-DRB1polymorphism determines the relative risk of antinuclear antibodies for disease progression in PBC2010
Author(s)
Nakamura M, Yasunami M, Kondo H, Horie H, Aiba Y, Komori A, Migita K, Yatsuhashi H, Ito M, Shimoda S, Ishibashi H; PBC Study Group in NHOSLJ
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Journal Title
Hepatol Res. May
Volume: 40(5)
Pages: 494-504
Peer Reviewed
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[Journal Article] Kyushu University Liver Disease Study Group.Pegylated interferon a-2b plus ribavirin for older patients with chronic hepatitis2010
Author(s)
Kainuma M, Furusyo N, Kajiwara E, Takahashi K, Nomura H, Tanabe Y, Satoh T, Maruyama T, Nakamuta M, Kotoh K, Azuma K, Shimono J, Shimoda S, Hayashi J
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Journal Title
C. World J Gastroenterol
Volume: 16(35)
Pages: 4400-9
Peer Reviewed
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