2004 Fiscal Year Final Research Report Summary
Investigation of mechanisms responsible for the hematopoietic progenitor cell mobilization to improve the efficiency and safety of hemopoietic progenitor cell collection.
| Project/Area Number |
15591030
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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 |
Hematology
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| Research Institution | Fukuoka University |
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Principal Investigator |
TAKAMATSU Yasushi Fukuoka University, Hospital, Assistant Professor, 病院, 助手 (50320297)
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| Co-Investigator(Kenkyū-buntansha) |
TAMURA Kazuo Fukuoka University, School of Medicine, Professor, 医学部, 教授 (60145422)
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| Project Period (FY) |
2003 – 2004
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| Keywords | Hematopoietic progenitor cell mobilization / G-CSF / CXCR4 / SDF-1 / Neutrophil Elastase / Cathepsin G / Thrombocytopenia / Splenomegaly |
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| Research Abstract |
Hematopoietic progenitor cells (HPCs) normally reside in the bone marrow (BM) but can be mobilized into the peripheral blood (PB) after treatment with GCSF. These mobilized-HPCs have been widely used for the BPC transplantation in not only hematological malignancies but also solid tumors.
We investigated the mechanism underling G-CSF-induced HPC mobilization. Granulocyte precursors accumulate in the BM during mobilization induced by GCSF, leading to the accumulation of active neutrophil proteases in this tissue. : HPC mobilizaion by GCSF coincides in vivo with the cleavage of the N-terminus of the chemokine receptor CXCR4 on HPCs resident in the BM and mobilized into the PB. This cleavage of CXCR4 on mobilized HPCs results in the loss of chemotaxis in response to the CXCR4 ligand, the chemokine stromal cell-derived factor-1 (SDF-1). Furthermore, the concentration of SDF-1 decreased in vivo in the BM of mobilized mice, and this decrease coincided with the accumulation of serine proteases
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able,to directly cleave and inactivate SDF-1. Since both SDF-1 and its receptor, CXCR4, are essential for the homing and retention of HPCs in the BM, the proteolytic degradation of SDF-1, together with that of CXCR4, could represent a critical step leading to the mobilization of HPCs into the PB in response to GCSF.
The clinical use of G-CSF for HPC mobilization results in a reduction in platelet numbers. However, the mechanisms responsible for G-CSF-induced thrombocytopenia have not been determined. Splenomegaly is observed in mice treated with G-CSF and splenic rupture is reported in human during G-CSF-induced HPC mobilization. Since splenic pooling of the platelets is known to be the mechanism of thrombocytopenia in patients wit splenomegaly, we hypothesized that hypersplenism might be the cause of G-CSF-induced thrombocytoppeia. Since transfused platelets should be cleared rapidly from-blood stream under the hypersplenic state, we underwent platelet survival studies in both G-CSF-treated and control mice. Contrary to our expectations, there was no significant difference in the life span of the labeled platelets between G-CSF-treated and control mice. To clarify the direct role of spleen on the reduction in platelet numbers in G-CSF-injected mice, we removed spleen surgically and investigated their platelet kinetics. Platelet counts of the splenectomized mice decreased significantly following 7-day-treatment of GCSF. These data demonstrate that G-CSF treatment induces splenomegaly as well as reduction of platelet numbers, however hypersplenism is not the cause of thrombocytopenia. Less
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Research Products
(17 results)
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[Journal Article] Conditioning with targeted busulfan for autologous peripheral blood stem cell transplantation for acute myelogenous leukemia in an XYY male.2005
Author(s)
Sada E, Henzan H, Ohtani R, Takase K, Miyamoto T, Fukuda T, Nagafuji K, Yamauchi K, Takamatsu Y, Inaba S, Harada M
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Journal Title
Am J Hematol 78
Pages: 55-58
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Clinical results of allogeneic hemopoietic stem cell transplantation for hematological disorders.2004
Author(s)
Takamatsu Y, Kumagawa M, Suzuki K, Wakamatsu S, Ishizu M, Shirahama S, Kawano T, Shirahashi A, Shishime M, Nibu K, Suzumiya J, Tamura K
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Journal Title
Med Bull Fukuoka Univ 31
Pages: 97-106
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Differential chemokine, chemokine receptor, cytokine, cytokine receptor expression in pulmonary adenocarcinoma : Diffuse down-regulation is associated with immune evasion and brain metastasis.2003
Author(s)
Ohshima K, Hamasaki M, Makimoto Y, Yoneda S, Fujii A, Takamatsu Y, Nakashima M, Watanabe T, Kawahara K, Kikuchi M, Shirakusa T
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Journal Title
Int J Oncol 23
Pages: 965-973
Description
「研究成果報告書概要(欧文)」より
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