Analysis of mechanisms responsible for clonal expansion of PNH-type hematopoietic stem cells mediated by autoreactive T cells in patients with bone marrow failure
| Project/Area Number |
17390275
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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 |
Hematology
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| Research Institution | Kanazawa University |
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Principal Investigator |
NAKAO Shinji Kanazawa Univesity, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (70217660)
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| Co-Investigator(Kenkyū-buntansha) |
TAKAMI Akiyoshi Kanazawa University Hospital, Instructor, 医学部附属病院, 助手 (80324078)
YAMAZAKI Hirohito Kanazawa University Hospital, Instructor, 医学部附属病院, 助手 (50361994)
KONDO Yukio Kanazawa University Hospital, Instructor, 医学部附属病院, 助手 (10322116)
YACHIE Akihiro Kanazawa Univesity, Graduate School of Medical Science, Professor, 医学系研究科, 教授 (40210281)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥15,300,000 (Direct Cost: ¥15,300,000)
Fiscal Year 2006: ¥6,800,000 (Direct Cost: ¥6,800,000)
Fiscal Year 2005: ¥8,500,000 (Direct Cost: ¥8,500,000)
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| Keywords | aplastic anemia / DRS / moesin / paroxysmal nocturnal hemoglobinuria / autoantibody / cytotoxic T cell / 細胞障害性T細胞 |
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| Research Abstract |
In an attempt to determine whether CD4^+ T cells specific to diazepam-binding inhibitor protein-1 (DRS-1) contribute to the survival advantage of paroxysmal nocturnal hemoglobinuria (PNH)-type stem cells, we established a lymphobastoid cell line with PIG-A mutation from an aplastic anemia (AA) patients showing a high titer antibodies speicific to DRS-1. We tried to transfect the PNH-type LCL cells with DRS-1 cDNA using various methods such as retroviral vectors and electroporation to use them as a target of DRS-1 specific CD4^+ T cells. However, all the methods failed to induce expression of DRS-1 gene in LCL cells, probably due to inhibitory mechanisms for the DRS-1 expression inherent to B lymphocytes. Thus, we suspended this experiments and focused on another candidate autoantigen, moesin.
We screened the sera of AA patients possessing small populations of PNH-type cells for the presence of antibodies (Abs) which recognize proteins derived from a leukemia cell line, UT-7. Immunoblott
… More
ing using proteins derived from lysates or culture supernatants of UT-7 cells revealed the presence of IgG Abs specific to an 80 kD protein. Peptide mass fingerprinting identified this 80 kD protein as moesin. Enzyme-linked immunosorbent assay (ELISA) using recombinant moesin showed high titers of anti-moesin Abs in 25 (37%) of 67 AA patients. Moesin was secreted from several myeloid leukemia cell lines other than UT-7, such as OUN-1 and K562, as an exosomal protein. The presence of anti-moesin Abs was significantly correlated with the presence of PNH-type cells and anti-diazepam-binding inhibitor-related protein-1 (DRS-1) Abs. AA patients that did not show any of these three markers tended to respond poorly to immunosuppressive therapy. These findings suggest that a B-cell response to moesin, possibly derived from hematopoietic cells, frequently occurs in patients with AA and that detection of anti-moesin Abs in combination with other markers may be useful in diagnosing immune pathophysiology in AA patients. Less
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Report
(3 results)
Research Products
(33 results)
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[Journal Article] Specific antibodies to moesin, a membrane-cytoskeleton linker protein, are frequently detected in patients with acquired aplastic anemia.2007
Author(s)
Takamatsu H, Feng X, Chuhjo T, Lu X, Sugimori C, Okawa K, Yamamoto M, Iseki S, Nakao S
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Journal Title
3Iood. 109(6)
Pages: 2514-2520
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Roles of DRB1 * 1501 and DRB1*1502 in the pathogenesis of aplastic anemia.2006
Author(s)
Sugimori C, Yamazaki H, Feng X, Mochizuki K, Kondo Y, Takami A, Chuhjo T, Kimura A, Teramura M, Mizoguchi H, Omine M, Nakao S
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Journal Title
ExpHematol. 35(1)
Pages: 13-20
NAID
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Impact of human leucocyte antigen mismatch on graft-versus-host disease and graft failure after reduced intensity conditioning allogeneic haematopoietic stem cell transplantation from related donors.2005
Author(s)
Teshima T, Matsuo K, Matsue K, Kawano F, Taniguchi S, Hara M, Hatanaka K, Tanimoto M, Harada M, Nakao S, Abe Y, Wake A, Eto T, Takemoto Y, Imamura M, Takahashi S, Ishida Y, Kanda Y, Kasai M, Takaue Y
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Journal Title
3rJHaematol. 130(4)
Pages: 575-587
Description
「研究成果報告書概要(欧文)」より
Related Report
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[Journal Article] Isolated hyperkalemia associated with cyclosporine administration in allogeneic stem cell transplantation for renal cell carcinoma.2005
Author(s)
Takami A, Asakura H, Takamatsu H, Yamazaki H, Arahata M, Hayashi T, Shibayama M, Onto M, Yoshida T, Namiki M, Nakao S
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Journal Title
IntJHematol. 81
Pages: 159-161
NAID
Description
「研究成果報告書概要(欧文)」より
Related Report
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