| Project/Area Number |
21390364
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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 |
General surgery
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| Research Institution | Kyushu University |
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Principal Investigator |
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| Co-Investigator(Kenkyū-buntansha) |
UEDA Yasuji 千葉大学, 医学研究院, 客員准教授 (80165662)
吉田 久美 九州大学, 大学院・薬学研究院, 助教 (80553271)
上田 泰次 千葉大学, 医学研究院, 客員准教授 (20184939)
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| Co-Investigator(Renkei-kenkyūsha) |
MAEHARA Yoshihiko 九州大学, 医学研究院, 教授 (80165662)
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| Project Period (FY) |
2009 – 2011
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| Project Status |
Completed (Fiscal Year 2011)
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| Budget Amount *help |
¥17,680,000 (Direct Cost: ¥13,600,000、Indirect Cost: ¥4,080,000)
Fiscal Year 2011: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000)
Fiscal Year 2010: ¥5,980,000 (Direct Cost: ¥4,600,000、Indirect Cost: ¥1,380,000)
Fiscal Year 2009: ¥6,630,000 (Direct Cost: ¥5,100,000、Indirect Cost: ¥1,530,000)
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| Keywords | 実験外科学 / 樹状細胞 / がん免疫 / 大量培養 / 腹水がん / 胸膜播種 / サイトカイン / センダイウイルス |
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| Research Abstract |
Though DC-based cancer immunotherapy has been suggested as a potential treatment for various kinds of malignancies, its clinical efficacies are still insufficient in many human trials. Especially, malignant ascites(MA) is a highly intractable and immunotherapy-resistant state of advanced gastrointestinal and ovarian cancers.
First, floating cultivation of mononuclear cells from cancer patients under an optimized cytokine cocktail(GM-CSF/SCF) led these cells to stable proliferation and to DC differentiation. As are seen in conventional DCs, expanded DCs showed dendrites after maturation, and endocytotic activities. Expanded DCs also expressed HLA-DR, adhesion molecules, and co-stimulatory molecules and produced inflammatory cytokines as well as conventional DCs did. Functionally, MLR assay revealed that expanded DCs could stimulate allogenic T-cell proliferation to the same extent as conventional DCs.
Next, using a murine model of MA with CT26 colon cancer cells, we here determined that the imbalance between the VEGF-A and its decoy receptor, soluble fms-like tryrosine kinase receptor-1(sFLT-1), was a major cause of MA resistance to DC-based immunotherapy. We found that the ratio of VEGF-A/sFLT-1 was increased not only in murine but also in human MA, and F-gene. deleted recombinant Sendai virus(rSeV/dF)-mediated secretion of human sFLT-1 by DCs augmented not only the activity of DCs themselves, but also dramatically improved the survival of tumor-bearing animals associated with enhanced CTL activity and its infiltration to peritoneal tumors.
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