| Project/Area Number |
12213025
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| Research Category |
Grant-in-Aid for Scientific Research on Priority Areas
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| Allocation Type | Single-year Grants |
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| Review Section |
Biological Sciences
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| Research Institution | University of Tokyo |
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Principal Investigator |
TAKATSU Eyoshi Institute of Medical Science, Division of Immunology, Professor, 医科学研究所, 教授 (10107055)
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| Co-Investigator(Kenkyū-buntansha) |
TAMURA Toshiki Institute of Medical Science, Division of Immunology, Research Associate, 医科学研究所, 助手 (40291306)
KARIYONE Ai Institute of Medical Science, Division of Immunology, Research Associate, 医科学研究所, 助手 (50114450)
高木 智 東京大学, 医科学研究所, 助教授 (10242116)
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| Project Period (FY) |
2000 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥52,100,000 (Direct Cost: ¥52,100,000)
Fiscal Year 2004: ¥10,300,000 (Direct Cost: ¥10,300,000)
Fiscal Year 2003: ¥10,700,000 (Direct Cost: ¥10,700,000)
Fiscal Year 2002: ¥11,000,000 (Direct Cost: ¥11,000,000)
Fiscal Year 2001: ¥10,100,000 (Direct Cost: ¥10,100,000)
Fiscal Year 2000: ¥10,000,000 (Direct Cost: ¥10,000,000)
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| Keywords | Ag85B / Peptide-25 / Thl-indicing Peptide / I-A restriction / IFN-γ / Adjuvant Activity / Transgenic mice / Cytotoxic Activity / CLT / CpG DNA / TCRVβ11 / 結核菌 / α抗原 / ヘルパーT細胞 / ペプチド-25 / IFNγ / CTL |
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| Research Abstract |
The effector CD8^+ T cells recognize MHC class I binding altered self-peptides expressed in tumor cells. Although the requirement for CD4^+ Th1 cells in regulating CD8^+ T cells has been documented, their target epitopes and functional impact in antitumor responses remain unclear. We examined whether a potent immunogenic peptide of Mycobacterium (M.) tuberculosis eliciting Thl immunity contributes to the generation of CD8^+ T cells and to protective antitumor immune responses to unrelated tumor-specific antigens. Peptide-25, a major Th epitope of Ag85B from M. tuberculosis preferentially induced CD4^+ Thl cells in C57BL/6 mice and showed an augmenting effect on Thl generation for coimmunized unrelated antigenic peptides. Coimmunization of mice with Peptide-25 and OVA or Peptide-25 and B16 melanoma peptide (TRP-2) for MHC class I led to a profound increase in CD8^+ T cells specific for OVA and TRP-2 peptides, respectively. This heightened response depended on Peptide-25 specific CD4^+ I
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FN-y-producing Th1 cells. In tumor protection assays, immunization with Peptide-25 and OVA resulted in the enhancement of CD8^+ cytotoxic cell generation specific for OVA and the growth inhibition of EL-4 thymoma expressing OVA peptide leading to the tumor rejection, that were not achieved by immunization with OVA alone. Peptide-25 reactive Thl cells counteractivated dendritic cells (DCs) in the presence of Peptide-25 leading them to activate and present OVA peptide to CD8^+ cytotoxic T cells. This result indicates that Peptide-25 not only induces a Thl-response by itself but also induces Thl-inducing activation of DCs through interactions with CD4^+ T cells. Therefore, we generated TCR transgenic mice (P25 TCR-Tg) expressing TCR a-and β-chains of Peptide-25-reactive cloned T cells and analyzed Thl development of CD4^+ T cells from P25 TCR-Tg to elucidate cellular and molecular mechanisms of the induction of Thl differentiation by Peptide-25. Naive CD4^+ T cells from P25 TCR-Tg preferentially develop Thl cells upon Peptide-25 stimulation in the presence of I-A^b splenic antigen-presenting cells under neutral conditions. Peptide-25-induced Thl differentiation is observed even in the presence of anti-IFN-y and anti-IL-12. Furthermore, Peptide-25-loaded I-A^b-transfected Chinese hamster ovary cells (Peptide-25-I-A^b-CHO) induce Thl differentiation of naive CD4^+ T cells from P25 TCR-Tg in the A^bsence of IFN-y or IL-12. Three hours after the TCR stimulation with Peptide-25-I-A^b-CHO, transient T-bet up-regulation and suppression of GATA-3 expression were observed by quantitative RT-PCR, both of which were independent of IFN-y and IL-12. These results imply that interaction between Peptide-25/I-A^b and TCR may primarily influence determination of the fate of naive CD4^+ T cells in their differentiation towards the Th1 subset. Taken together, these results indicate that Peptide-25 exerts potent adjuvant activity and provides efficient help for CTL induction against tumor antigen. Less
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