2004 Fiscal Year Final Research Report Summary
Assessment of immune modulation by Notch signaling-exploration of immunomodulatory intervention targeting Notch system.
| Project/Area Number |
14370300
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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 | The University of Tokyo |
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Principal Investigator |
CHIBA Shigeru The University of Tokyo, Faculty of Medicine, Associate Professor, 医学部附属病院, 講師 (60212049)
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| Co-Investigator(Kenkyū-buntansha) |
MOTOKURA Toru The University of Tokyo, Faculty of Medicine, Lecturer, 医学部附属病院, 講師 (00192823)
OGAWA Seishi The University of Tokyo, Faculty of Medicine, visiting Associate Professor, 医学部附属病院, 寄付講座教員 (60292900)
KANDA Yoshinobu The University of Tokyo, Faculty of Medicine, Research Associate, 医学部附属病院, 助手 (30334379)
SUZUKI Takahiro The University of Tokyo, Faculty of Medicine, visiting Associate Professor, 医学部附属病院, 寄付講座教員 (40345210)
KUMANO Keiki The University of Tokyo, Faculty of Medicine, Project Researcher, 医学部附属病院, 研究拠点形成特任研究員
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| Project Period (FY) |
2002 – 2004
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| Keywords | Notch / allogeneic hematopoietic stem cell transplantation / graft-versus-host disease / transgenic mouse / MHC class II promoter / Jagged1 / conditional knockout mouse / innate immunity |
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| Research Abstract |
Signaling through Notch receptors regulates various aspects of immune system, such as development of T cells in the thymus, formation of marginal zone B cells in the spleen, Th1/Th2 differentiation and regulation of T cell activation. Therefore, it is expected that we will be able to establish a new technology to regulate immune reconstitution after allogeneic hematopoietic stem cell transplantation if we can modulate Notch signaling using its agonists or antagonists. In this study, we aimed at obtaining basic data supporting establishment of a method to prevent graft-versus-host disease (GVHD) by Notch signaling modulation.
We have generated transgenic mice expressing wild-type and dominant-negative form of Notch ligands under the MHC class I and MHC class II promoters, and characterized the phenotype and function of lymphocytes. We found that the T cell activation by the mixed lymphocyte culture was markedly reduced in the transgenic mice expressing wild-type Jagged1, one of the five known Notch ligands, under the MHC class II promoter. Using these mice as donors and recipients in the acute GVHD, rejection and chronic GVHD models, ongoing are allogeneic transplantation experiments. Based on the results deriving from these experiments, we plan to study, using Notch agonists and antagonists, how the modulation of individual Notch system affects development of GVHD.
Furthermore, we found that Notch2 signaling regulates the expression of surface molecules which are considered to be important for the innate immunity, using Notch2 conditional knockout mice. Based on this finding, we are currently studying how the signaling through Notch2 receptor plays a role in the T cell-independent antibody production by the marginal zone B cells.
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Research Products
(12 results)
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[Journal Article] AML-1 is required for megakaryocytic maturation and lymphocytic differentiation, but not for maintenance of hematopoietic stem cells in adult hematopoiesis.2004
Author(s)
Ichikawa M, Asai T, Saito T, Yamamoto G, Seo S, Yamazaki I, Yamagata T, Mitani K, Chiba S, Ogawa S, Kurokawa M, Hirai H.
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Journal Title
Nature Med 10
Pages: 299-304
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Notch2 Is Preferentially Expressed in Mature B Cells and Indispensable for Marginal Zone B Lineage Development.2003
Author(s)
Saito T, Chiba S, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto GS Seo S, Kumano K, Nakagami-Yamaguchi E, Hamada Y, Aizawa S, Hirai H.
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Journal Title
Immunity 18
Pages: 675-685
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Notch1 but Not Notch2 Is Essential for Generating Hematopoietic Stem Cells from Endothelial Cells.2003
Author(s)
Kumano K, Chiba S, Kunisato A, Sata M, Saito T, Nakagami-Yamaguchi E, Yamaguchi T, Masuda S, Shimizu K, Takahashi T, Ogawa S, Hamada Y, Hirai H.
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Journal Title
Immunity 18
Pages: 699-711
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] HES-1 preserves purified hematopoietic stem cells ex vive and accumulates side population cells in vivo.2003
Author(s)
Kunisato A, Chiba S, Nakagami-Yamaguchi E, Kumano K, Saito T, Masuda S, Yamaguchi T, Osawa M, Kageyama R, Nakauchi H, Nishikawa M, Hirai H.
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Journal Title
Blood 101
Pages: 1777-1783
Description
「研究成果報告書概要(欧文)」より
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