2007 Fiscal Year Final Research Report Summary
Comprehensive analyses of therapeutic strategy against chronic active Epstein-Barr virus(EBV) infection
| Project/Area Number |
18591190
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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 |
Pediatrics
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| Research Institution | Kochi University |
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Principal Investigator |
WAKIGUCHI Hiroshi Kochi University, Department of Pediatrics, Professor (10116519)
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| Co-Investigator(Kenkyū-buntansha) |
MEADA Akihiko Kochi University, Department of Pediatrics, Instructor (50335931)
IMAI Shosuke Kochi University, Department of Microbiology and Infection, Professor (60232592)
FUJIEDA Mikiya Kochi University, Department of Pediatrics, Associate Professor (60209020)
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| Project Period (FY) |
2006 – 2007
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| Keywords | Enstein-Barr virus(EBV) / infectious diseases / gene therapy / CTL / cytokines |
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| Research Abstract |
The aim of this study was to identify the cellular genes associated with or responsible for the oncogenesisi of Epstein-Barr virus (EBV) in EBV-positive T, MC and epithelial tumor cells, by utilizing dominant-negative EBNA1 (DNE1; Mal. Ther., 11(4): 578-90, 2005)that can eradicate EBV episomes from cells. We prepared isogenic pairs of EBV-positive and -negative NK- and T-cell lines by DNE1 transduction and compared their malignant grade. Concomitantly alterations of cellular gene expression in those cell pairs were comprehensively assessed with the multi-cytokine assay system, thereby elucidating the role(s)of EBV in malignant conversion. Further, we analysed EBV-specific cytotoxic T-cells (EBV-CTL) by a tetramer assay using 3 EBV-antigens, i.e., BRLF1, BMLF1 and EBNA3. The results obtained are as follows.
1. Adenovirus vector-mediated transduction of our DNE1 successfully eradicated EBV episomes from the majority of naturally EBV-positive T-cell and NK-cell lymphoma and epithelial tumo
… More
r cell lines in a few days.
2. The DNE1-induced EBV-lost T-cells and NK-cells showed a striking suppression of their malignant phenotypes, such as prolongation of doubling time and loss of anchorage-independent growth potential, compared with parental EBV-positive T-cell and NK-cell tumors. In a part of the EBV-lost T-cells and NK-cells, loss of viral genome also brought about cell death.
3. The EBV-lost T-cells and NK-cells showed significantly decreased production of some cytokines, such as interleukin-9, compared with the parental EBV-positive T-cell and NK-cell tumors. Conversely, the production levels of another cytokine was also found to be upregulated in the EBV-lost T-cells.
These results indicate that the EBV-dependent malignant phenotypes in T- and NK-cells and perhaps also in epithelial cells, as in B-cell lymphomas, are associated, at least partly, with upregulation (i.e., the autocrine mechanism) and/or down regulation of certain cytokines. We are planning to explore precisely the mechanisms of cytokine gene control and specific effects on EBV oncogenesis. Less
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