2003 Fiscal Year Final Research Report Summary
DEVELOPMENT OF IMMUNOTHERAPY To HEMATOLOGIC MALIGNANCIES
| Project/Area Number |
13557080
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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 | 展開研究 |
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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, 助教授 (60212049)
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| Co-Investigator(Kenkyū-buntansha) |
高橋 強志 東京大学, 医学部附属病院, 助手 (70332608)
小川 誠司 東京大学, 医学部附属病院, 客員助教授(常勤形態) (60292900)
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| Project Period (FY) |
2001 – 2003
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| Keywords | NKT cell / Vα24 / CD8+ / α-galactosy ceramide / CD1d / T lymphoblastic leukemia / リンパ腫 |
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| Research Abstract |
We aimed at development of immunotherapy to hematological malignancies using NKT cells. Human NKT cells, ligands for which are CD1d/glycolipid complexes, utilize Va24 in TCR. As in mouse NKT cells, presence of CD4-CD8-and CD4+ subsets have been known in human NKT cells. In this project, we now newly identified the CD8+ subset. Moreover, we clarified the differences in the function among these subsets, particulaily the difference in the cytokine production profile.
We here found that human T cell neoplasms frequently express CD1d at a high level and that Va24NKT cells show anti-tumor activity against the CD1d+ T cell neoplastic cells. A glycolipid, a-galactosyl ceramide (a-GalCer), enhanced the anti-tumor activity of NKT cells in vitro. Therefore, direct administration of a-GalCer or administration of NKT cells that are expanded in vitro by a-GalCer could be a potential therapeutic option for T cell neoplastic diseases.
To further investigate such a possibility, we established an in vivo model for NKT cell-based anti-tumor therapy. A mouse precursor T cell tumor cell line, EL-4 expresses CD1d only at a weak level. We introduced CD1d cDNA into EL-4 and obtained cell lines overexpressing CD1d at various levels. In vitro, NKT-based cytotoxicity was stronger for EL-4 expressing CD1d at higher levels. Then, these cell lines were injected into syngenic B57BL/6 mice. We found that mice injected with EL-4 lines expressing higher levels of CD1d survived longer periods of time and that the survival time was extended by the administration of a-GalCer. These results indicate that endogenous NKT cells inhibit tumor growth through CD1d interaction.
We now creating a protocol on a clinical trial for T cell lymphoblastic leukemia using NKT cells.
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[Publications] Saito T, ChibaS, Ichikawa M, Kunisato A, Asai T, Shimizu K, Yamaguchi T, Yamamoto G, Seo S, Kumano K, Nakagami-Yamaguchi E, Hamada Y, Aizawa S, Hirai H.: "Notch2 Is Preferentially Expressed in Mature B Cells and Indispensable for Marginal Zone B Lineage Development."Immunity. 18. 675-685 (2003)
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