| Project/Area Number |
15390325
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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 |
Pediatrics
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| Research Institution | KYUSHU UNIVERSITY |
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Principal Investigator |
HARA Toshiro Kyushu University, Department of Pediatrics, Professor, 大学院・医学研究院, 教授 (40150445)
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| Co-Investigator(Kenkyū-buntansha) |
KUSUHARA Koichi Kyushu University, Department of Pediatrics, Associate Professor, 大学院・医学研究院, 助教授 (20243941)
TAKADA Hidetoshi Kyushu University, Department of Pediatrics, Assistant Professor, 大学病院, 講師 (70294931)
NOMURA Akihiko Kyushu University, Department of Pediatrics, Research Associate, 大学病院, 助手 (00325531)
SAKAI Yasunari Kyushu University, Department of Pediatrics, Research Associate, 大学病院, 助手 (10380396)
YOSHIKAI Yasunobu Kyushu University, Institute of Bioregulation, Professor, 生体防御医学研究所, 教授 (90158402)
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| Project Period (FY) |
2003 – 2005
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| Project Status |
Completed (Fiscal Year 2005)
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| Budget Amount *help |
¥14,700,000 (Direct Cost: ¥14,700,000)
Fiscal Year 2005: ¥4,300,000 (Direct Cost: ¥4,300,000)
Fiscal Year 2004: ¥5,000,000 (Direct Cost: ¥5,000,000)
Fiscal Year 2003: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | intracellular bacteria / macrophage / Mycobacterium / osteopontin / CXCL7 / Sendai virus vector / dendritic cell / T-bet / 結核 / 細胞免疫療法 / IFN-γ / 細胞遺伝子療法 / 結核感染マウスモデル |
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| Research Abstract |
1.Analysis of host responses to intracellular bacteria
Granulocyte-macrophage colony-stimulating factor (GM-CSF)-induced human monocyte-derived macrophage (GM-Mφ) or macrophage CSF (M-CSF)-induced human monocyte-derived Mφ (M-Mφ) are distinct in terms of the resistance to Mycobacterium tuberculosis. To elucidate the role of molecules involved in the functional differences between these Mφs, we investigated the gene expression profiles using microarray. After culture of CD14^+ monocytes with CSFs, Mφs were cultured with or without bacillus Calmette-Guerin (BCG) (GM-Mφ-BCG and M-Mφ-BCG). The gene expression profiles from these cells were compared. Chemokines highly expressed in M-Mφs were selected and evaluated for anti-mycobacterial activity and superoxide production. FN1 and FCGR2B were the most up-regulated genes in GM-Mφ and M-Mφ, respectively. After stimulation with BCG, three chemokine genes (Osteopontin (SPP1), CXC chemokine ligand 7(CXCL7) and CC chemokine ligand 11(CCL11)) were highly expressed in M-Mφ-BCG when compared to those in GM-Mφ-BCG. A significantly increased resistance to M. tuberculosis H37Ra was observed after the stimulation of GM-Mφ with SPP1 or CXCL7. Superoxide production levels of SPP1- or CXCL7-stimulated GM-Mφs were higher than those of GM-Mφs without stimulation. These results indicate that both SPP1 and CXCL7 might have a role in the resistance against mycobacteria, at least in part, through augmenting reactive oxygen intermediate production in Mφs.
2.Development of cell-mediated gene therapy
To conventional therapy-resistant TB patients, dendritic cell-mediated gene therapy was planned with Sendai virus vector having T-bet gene, which strongly induces Th1 development of T cells. At present, sufficient IFN-gamma production was not obtained. Further study will be necessary to perform cell-mediated gene therapy.
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