抗結核ワクチンの新戦略:潜伏感染、再燃を制御するワクチンの研究

2010 年度 研究成果報告書

• 研究課題/領域番号: 20390125
• 研究種目: 基盤研究(B)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 細菌学(含真菌学)
• 研究機関: 浜松医科大学
• 研究代表者: 小出 幸夫 浜松医科大学, 医学部, 理事 (30126809)
• 研究分担者: 永田 年 浜松医科大学, 医学部, 教授 (90275024) ; 辻村 邦夫 浜松医科大学, 医学部, 准教授 (10227407) ; 内嶋 雅人 浜松医科大学, 医学部, 助教 (20252174) ; 瀬戸 真太郎 浜松医科大学, 医学部, 助教 (50383203) ; 千田 金吾 浜松医科大学, 医学部, 准教授 (40197611) ; 須田 隆文 浜松医科大学, 医学部, 助教 (30291397) ; 加藤 秀樹 浜松医科大学, 医学部, 准教授 (30142053)
• 研究期間 (年度): 2008 – 2010
• キーワード: ワクチン / 結核菌 / 潜伏期 / 再燃

研究概要

結核菌が潜伏期特異的に発現する蛋白質群(DosR蛋白質群およびRpf蛋白質群)についてマウスで免疫原生を検討し、C57BL/6およびBALB/cの両系統においてT細胞応答を誘導できる抗原を7種類、同じく抗体産生を誘導できる抗原を3種類同定した。樹状細胞による抗原の取り込みを促進する新規ワクチン技術として、糖鎖被覆リポソームおよび分子融合型ワクチン(熱ショック蛋白質70またはケモカインMIP-1αと結核防御抗原との融合分子)を開発した。

研究成果

• [雑誌論文] Rab GTPases regulating phagosome maturation are differentially recruited to mycobacterial phagosomes. (2011)
  • 著者名/発表者名: 瀬戸真太郎, 辻村邦夫, 小出幸夫
  • 雑誌名: Traffic 12 ページ: 407-420
  • 査読あり
• [雑誌論文] A novel vaccine strategy to induce mycobacterial antigen-specific Th1 responses by utilizing the C-terminal domain of Heat Shock Protein 70. (2011)
  • 著者名/発表者名: Uto T,Tsujimura K, Uchijima M, Seto S, Nagata T, Suda T, Chida K, Nakamura H, Koide Y
  • 雑誌名: FEMS Immunol Med Microbiol 61 ページ: 189-196
  • 査読あり
• [雑誌論文] Differences in CD4^+CD25^+ regulatory T cell-depletion between Babesia microti and Babesia rodhaini infections in mice. (2010)
  • 著者名/発表者名: Yokoyama N, Ikehara Y, Tiwananthagorn W, Ota N, Igarashi I, Kojima N, Taguchi O, Tsujimura K
  • 雑誌名: J Protozool Res 20 ページ: 20-30
  • 査読あり
• [雑誌論文] Immunogenicity of dormancy-related antigens of Mycobacterium tuberculosis in DNA-vaccinated mice. (2010)
  • 著者名/発表者名: Yamamura Y, Seto S, Uchijima M, Hozumi H, Nagata T, Tsujimura K, Koide Y
  • 雑誌名: Procedia Vaccinology 3 ページ: 19-26
  • 査読あり
• [雑誌論文] Induction of specific CD8 T cells against intracellular bacteria by CD8 T-cell-oriented immunization approaches. (2010)
  • 著者名/発表者名: Nagata T, Koide Y
  • 雑誌名: J.Biomed.Biotechnol. 764542
  • 査読あり
• [雑誌論文] 結核菌に対するT細胞誘導ワクチンの試み (2010)
  • 著者名/発表者名: 永田年, 小出幸夫
  • 雑誌名: 日本細菌学雑誌 65 ページ: 309-324
• [雑誌論文] 結核菌抗原認識とT細胞免疫 (2010)
  • 著者名/発表者名: 辻村邦夫, 小出幸夫
  • 雑誌名: 結核 85 ページ: 509-514
• [雑誌論文] Identification of murine T-cell epitopes on low-molecular-mass secreted proteins (CFP11, CFP17, and TB18.5) of Mycobacterium tuberculosis. (2010)
  • 著者名/発表者名: Eweda G, Suzuki D, Nagata T, Tsujimura K, Koide Y
  • 雑誌名: Vaccine 28 ページ: 4616-4625
  • 査読あり
• [雑誌論文] Differential recruitment of CD63 and Rab7-interacting-lysosomal-protein to phagosomes containing Mycobacterium tuberculosis in macrophages. (2010)
  • 著者名/発表者名: Seto S, Matsumoto S, Tsujimura K, Koide Y
  • 雑誌名: Microbiol Immunol 54 ページ: 170-174
  • 査読あり
• [雑誌論文] The herbal medicine compound falcarindiol from Notopterygii Rhizoma suppresses dendritic cell maturation. (2010)
  • 著者名/発表者名: Mitsui S, Torii K, Fukui H, Tsujimura K, Maeda A, Nose M, Nagatsu A, Mizukami H, Morita A
  • 雑誌名: J Pharmacol Exp Ther 333 ページ: 954-960
  • 査読あり
• [雑誌論文] Identification of HLA-DR4-restricted T-cell epitope on MPT51 protein, a major secretory protein derived from Mycobacterium tuberculosis using MPT51 overlapping peptides screening and DNA vaccination. (2010)
  • 著者名/発表者名: Wang L-X, Nagata T, Tsujimura K, Uchijima M, Seto S, Koide Y
  • 雑誌名: Vaccine 28 ページ: 2026-2031
  • 査読あり
• [雑誌論文] Characterization of murine T-cell epitopes on mycobacterial DNA-binding protein 1 (MDP1) using DNA vaccination. (2010)
  • 著者名/発表者名: Suzuki D, Nagata T, Eweda G, Matsumoto S, Matsumoto M, Tsujimura K, Koide Y
  • 雑誌名: Vaccine 28 ページ: 2020-2025
  • 査読あり
• [雑誌論文] Etanercept treatment reduces the serum levels of interleukin-15 and interferon-gamma inducible protein-10 in patients with rheumatoid arthritis. (2010)
  • 著者名/発表者名: Ichikawa T, Kageyama Y, Kobayashi H, Kato N, Tsujimura K, Koide Y
  • 雑誌名: Rheumatol Int 30 ページ: 725-730
  • 査読あり
• [雑誌論文] A novel positive feedback loop between Cyclin-dependent kinase 1 (CDK1) and CHK1 in the nucleus during the G2/M transition. (2009)
  • 著者名/発表者名: Enomoto M, Goto H, Tomono Y, Kasahara K, Tsujimura K, Kiyono T, Inagaki M
  • 雑誌名: J Biol Chem 284 ページ: 34223-34230
  • 査読あり
• [雑誌論文] Induction of anti-tumor immune responses with oligomannose-coated liposomes targeting to peritoneal macrophages. (2009)
  • 著者名/発表者名: Tsujimura K, Ikehara Y, Nagata T, Koide Y, Kojima N
  • 雑誌名: Procedia Vaccinology 1 ページ: 127-134
  • 査読あり
• [雑誌論文] Dissection of Rab7 localization on Mycobacterium tuberculosis phagosome. (2009)
  • 著者名/発表者名: Seto S, Matsumoto S, Ohta I, Tsujimura K, Koide Y
  • 雑誌名: Biochem Biophys Res Commun 387 ページ: 272-277
  • 査読あり
• [雑誌論文] Mucosal vaccine using CTL epitope-pulsed dendritic cell confers protection for intracellular pathogen. (2009)
  • 著者名/発表者名: Ozawa Y, Suda T, Nagata T, Hashimoto D, Nakamura Y, Enomoto N, Inui N, Koide Y, Nakamura H, Chida K.
  • 雑誌名: Am J Respir Cell Mol Biol 41 ページ: 440-448
  • 査読あり
• [雑誌論文] HapMap scanning of novel human minor histocompatibility antigens. (2009)
  • 著者名/発表者名: Kamei M, Nannya Y, Torikai H, Kawase T, Taura K, Inamoto Y, Takahashi T, Yazaki M, Morishima S, Tsujimura K, Miyamura K, Ito T, Togari H, Riddell SR, Kodera Y, Morishima Y, Takahashi T, Kuzushima K, Ogawa S, Akatsuka Y
  • 雑誌名: Blood 113 ページ: 5041-5048
  • 査読あり
• [雑誌論文] The cellular niche of Lesteria monocytogenes infection changes rapidly in the spleen. (2009)
  • 著者名/発表者名: Aoshi T, Carrero JA, Konjufca V, Koide Y, Unanue ER, Miller MJ
  • 雑誌名: Eur J Immunol 39 ページ: 417-425
  • 査読あり
• [雑誌論文] Bacterial entry to the splenic white pulp initiates antigen presentation to CD8^+ T cells. (2008)
  • 著者名/発表者名: Aoshi T, Zinselmeyer BH, Konjufca V, Lynch JN, Zhang X, Koide Y, Miller MJ
  • 雑誌名: Immunity 29 ページ: 476-486
  • 査読あり
• [雑誌論文] Chemokine receptor-mediated delivery of mycobacterial MPT51 protein efficiently induces antigen-specific T-cell responses. (2008)
  • 著者名/発表者名: Uchijima M, Nagata T, Koide Y
  • 雑誌名: Vaccine 26 ページ: 5165-5169
  • 査読あり
• [雑誌論文] In vivo hierarchy of individual T-cell epitope-specific helper T-cell subset against an intracellular bacterium. (2008)
  • 著者名/発表者名: Nagata T, Aoshi T, Uchijima M, Koide Y
  • 雑誌名: Vaccine 26 ページ: 5123-5127
  • 査読あり
• [雑誌論文] Intratracheal administration of third-generation lentivirus vector encoding MPT51 from Mycobacterium tuberculosis induces specific CD8^+ T-cell responses in the lung. (2008)
  • 著者名/発表者名: Hashimoto D, Nagata T, Uchijima M, Seto S, Suda T, Chida K, Miyoshi H, Nakamura H, Koide Y
  • 雑誌名: Vaccine 26 ページ: 5095-5100
  • 査読あり
• [雑誌論文] Identification of an HLA-A*0201- restricted T-cell epitope on the MPT51 protein, a major secreted protein derived from Mycobacterium tuberculosis, by MPT51 overlapping peptide screening. (2008)
  • 著者名/発表者名: Aoshi T,Nagata T, Suzuki M, Uchijima M, Hashimoto D, Rafiei A, Suda T, Chida K, Koide Y
  • 雑誌名: Infect Immun 76 ページ: 1565-1571
  • 査読あり
• [雑誌論文] Effect of CD4^+CD25^+ regulatory T cell-depletion on acute lethal infection of mice with Trypanosoma congolense. (2008)
  • 著者名/発表者名: Namangala B, Yokoyama N, Ikehara Y, Taguchi O, Tsujimura K, Sugimoto C, Inoue N
  • 雑誌名: J Vet Med Sci 70 ページ: 751-759
  • 査読あり
• [雑誌論文] Epstein-Barr virus nuclear antigen 1-specific CD4^+ T cells directly kill Epstein-Barr virus-carrying natural killer and T cells. (2008)
  • 著者名/発表者名: Demachi-Okamura A, Ito Y, Akatsuka Y, Tsujimura K, Morishima Y, Takahashi T, Kuzushima K
  • 雑誌名: Cancer Sci 99 ページ: 1633-1642
  • 査読あり
• [雑誌論文] Identification of a human leukocyte antigen-A24-restricted T-cell epitope derived from interleukin-13 receptor α2 chain, a glioma-associated antigen. (2008)
  • 著者名/発表者名: Shimato S, Natsume A, Wakabayashi T, Tsujimura K, Nakahara N, Ishii J, Ito M, Akatsuka Y, Kuzushima K, Yoshida J
  • 雑誌名: J Neurosurg 109 ページ: 117-122
  • 査読あり
• [雑誌論文] Induction of regulatory dendritic cells by topical application of NF-κB decoy oligodeoxynucleotides. (2008)
  • 著者名/発表者名: Isomura I Shintani Y, Yasuda Y, Tsujimura K, Morita A
  • 雑誌名: Immunol Lett 119 ページ: 49-56
  • 査読あり
• [雑誌論文] Oligomannose- coated liposomes as a therapeutic antigen-delivery and an adjuvant vehicle for induction of in vivo tumor immunity. (2008)
  • 著者名/発表者名: Kojima N, Biao L, Nakayama T, Ishii M, Ikehara Y, Tsujimura K
  • 雑誌名: J Control Release 129 ページ: 26-32
  • 査読あり
• [雑誌論文] Interleukin-2 potentiation of cetuximab antitumor activity for epidermal growth factor receptor-overexpressing gastric cancer xenografts through antibody- dependent cellular cytotoxicity. (2008)
  • 著者名/発表者名: Hara M, Nakanishi H, Tsujimura K, Matsui M, Yatabe Y, Manabe T, Tatematsu M
  • 雑誌名: Cancer Sci 99 ページ: 1471-1478
  • 査読あり
• [雑誌論文] The DNA demethylating agent 5-aza-2'-deoxycytidine activates NY-ESO-1 antigenicity in orthotopic human glioma. (2008)
  • 著者名/発表者名: Natsume A, Wakabayashi T, Tsujimura K, Shimato S, Ito M, Kuzushima K, Kondo Y, Sekido Y, Kawatsura H, Narita Y, Yoshida J
  • 雑誌名: Int J Cancer 122 ページ: 2542-2553
  • 査読あり
• [雑誌論文] Identification of human minor histocompatibility antigens based on genetic association with highly parallel genotyping of pooled DNA. (2008)
  • 著者名/発表者名: Kawase T, Nanya Y, Torikai H, Yamamoto G, Onizuka M, Morishima S, Tsujimura K, Miyamura K, Kodera Y, Morishima Y, Takahashi T, Kuzushima K, Ogawa S, Akatsuka Y
  • 雑誌名: Blood 111 ページ: 3286-3294
  • 査読あり
• [雑誌論文] Effective induction of anti-tumor immune responses with oligomannose-coated liposome targeting to intraperitoneal phagocytic cells. (2008)
  • 著者名/発表者名: Ikehara Y, Shiuchi N, Kabata-Ikehara S, Nakanishi H, Yokoyama N, Takagi H, Nagata T, Koide Y, Kuzushima K, Takahashi T, Tsujimura K, Kojima N.
  • 雑誌名: Cancer Lett 260 ページ: 137-145
  • 査読あり
• [雑誌論文] 結核菌ファゴソームの成熟阻害機構
  • 著者名/発表者名: 瀬戸真太郎、辻村邦夫、小出幸夫
  • 雑誌名: 化学療法の領域 印刷中
• [雑誌論文] 結核菌の細胞内寄生メカニズム
  • 著者名/発表者名: 瀬戸真太郎、辻村邦夫、小出幸夫
  • 雑誌名: 日本臨床 印刷中
• [学会発表] Immunogenicity of latency-associated antigens of Mycobacterium tuberculosis in DNA-vaccinated mice. (2010)
  • 著者名/発表者名: Tsujimura K, Yamamura Y, Hozumi H, Seto S, Uchijima M, Koide Y
  • 学会等名: The 10th Kyungpook-Hamamatsu Joint Medical Symposium.
  • 発表場所: 浜松
  • 年月日: 20100000
• [学会発表] Proteomic analysis revealed the interaction of endoplasmic reticulum with the phagosomes containing Mycobacterium tuberculosis in macrophages. (2010)
  • 著者名/発表者名: Seto S, Tsujimura K, Koide Y
  • 学会等名: The 10th Kyungpook- Hamamatsu Joint Medical Symposium.
  • 発表場所: 浜松
  • 年月日: 20100000
• [学会発表] Immune responses against dormancy-associated antigens of Mycobacterium tuberculosis in DNA- vaccinated mice. (2010)
  • 著者名/発表者名: Yamamura Y, Seto S, Uchijima M, Tsujimura K, Koide Y
  • 学会等名: 45th US-Japan Conference on Tuberculosis and Leprosy.
  • 発表場所: Cambridge/USA
  • 年月日: 20100000
• [学会発表] Proteomic analysis reveals the interaction of endoplasmic reticulum with the phagosome containing Mycobacterium tuberculosis. (2010)
  • 著者名/発表者名: Koide Y, Seto S, Tsujimura K
  • 学会等名: 45th US-Japan Conference on Tuberculosis and Leprosy.
  • 発表場所: Cambridge/USA
  • 年月日: 20100000
• [学会発表] Identification of murine T-cell epitopes on low-molecular-mass secreted proteins (CFP11, CFP17, and TB18.5) of Mycobacterium tuberculosis with DNA immunization. (2010)
  • 著者名/発表者名: Eweda G, Suzuki D, Nagata T, Tsujimura K, Koide Y
  • 学会等名: DNA vaccine 2010.
  • 発表場所: New Orleans/USA
  • 年月日: 20100000
• [学会発表] Immunogenicity of dormancy-related antigens of Mycobacterium tuberculosis in DNA-vaccinated mice. (2010)
  • 著者名/発表者名: Yamamura Y, Seto S, Uchijima M, Hodumi H, Nagata T, Tsujimura K, Koide Y
  • 学会等名: DNA vaccine 2010.
  • 発表場所: New Orleans/USA
  • 年月日: 20100000
• [学会発表] Genetic fusion of heat-shock protein 70 to a mycobacterial antigen enhances the antigen-specific T cell responses. (2009)
  • 著者名/発表者名: Uto T, Uchijima M, Seto S, Nagata T, Suda T, Chida K, Nakamura H, Tsujimura K, Koide Y
  • 学会等名: Vaccine 3rd Global Congress.
  • 発表場所: Singapore/Republic of Singapore
  • 年月日: 20090000
• [学会発表] Alternative localization of Rab GTPases to phagosome containing Mycobacterium tuberculosis in inhibition of phagolysosome biogenesis. (2009)
  • 著者名/発表者名: Seto S, Koide Y
  • 学会等名: 44th US-Japan Conference on Tuberculosis and Leprosy.
  • 発表場所: 福岡
  • 年月日: 20090000
• [学会発表] Cancer vaccine delivery using oligomannose coated liposomes. (2009)
  • 著者名/発表者名: Ikehara Y, Ikehara SK, Yokoyama N, Kuzushima K, Takahashi T, Kojima N, Tsujimura K
  • 学会等名: AACR 100th Annual Meeting.
  • 発表場所: Denver/USA
  • 年月日: 20090000
• [学会発表] Mycobacterium tuberculosis modulates the network of Rab GTPases in attenuation of phagosome maturation. (2009)
  • 著者名/発表者名: Seto S, Koide Y
  • 学会等名: Keystone symposium.
  • 発表場所: Keystone/USA
  • 年月日: 20090000
• [学会発表] Chk1 phosphorylation by Cyclin-dependent kinase 1 promotes mitotic entry. (2008)
  • 著者名/発表者名: Goto H, Enomoto M, Tomono Y, Kasahara K, Ikegami Y, Tsujimura K, Kiyono T, Inagaki M
  • 学会等名: 48th Annual Meeting of the American Society for Cell Biology.
  • 発表場所: San Francisco/USA
  • 年月日: 20080000
• [学会発表] Identification of HLA-DR4-restricted T-cell epitope on MPT51 protein, a major secreted protein derived from Mycobacterium tuberculosis using MPT51 overlapping peptides screening. (2008)
  • 著者名/発表者名: Nagata T, Wang L-X, Koide Y
  • 学会等名: DNA Vaccines 2008
  • 発表場所: Las Vegas/USA
  • 年月日: 20080000
• [学会発表] Characterization of murine T-cell epitopes on mycobacterial DNA-binding protein 1 (MDP1). (2008)
  • 著者名/発表者名: Suzuki D, Nagata T, Matsumoto S, Koide Y
  • 学会等名: DNA Vaccines 2008
  • 発表場所: Las Vegas/USA
  • 年月日: 20080000
• [学会発表] Effective induction of anti-tumor immune responses with oligomannose- coated liposomes targeting to intraperitoneal macrophages. (2008)
  • 著者名/発表者名: Tsujimura K, Ikehara Y, Nagata T, Koide Y, Kojima N
  • 学会等名: Vaccine 2nd Global Congress.
  • 発表場所: Boston/USA
  • 年月日: 20080000
• [学会発表] Mycobacterium tuberculosis modulates the network of Rab GTPases to inhibit phagolysosome biogenesis in macrophage. (2008)
  • 著者名/発表者名: Seto S, Koide Y
  • 学会等名: 第8回あわじ感染症・免疫フォーラム
  • 発表場所: 淡路
  • 年月日: 20080000
• [学会発表] Live Mycobacterium tuberculosis inhibits phagolysosome biogenesis in macrophages by modulating localization of Rab GTPase proteins on its phagosomes. (2008)
  • 著者名/発表者名: Seto S, Koide Y
  • 学会等名: 43rd US-Japan conference on tuberculosis and leprosy.
  • 発表場所: Baltimore/USA
  • 年月日: 20080000
• [学会発表] The DNA demethylating agent 5-aza-2'- deoxycytidine induces the expression of cancer-testis antigens in human gliomas : epigenetic target for tumor immunotherapy. (2008)
  • 著者名/発表者名: Natsume A, Wakabayashi T, Shimato S, Tsujimura K, Kuzushima K, Yoshida J
  • 学会等名: The 17th International Conference on Brain Tumor Research and Therapy.
  • 発表場所: 函館
  • 年月日: 20080000
• [図書] Chapter 15. Anti-infective vaccine strategies. Handbook of Listeria monocytogenes. (2008)
  • 著者名/発表者名: Nagata T, Koide Y
  • 総ページ数: 449-480
  • 出版者: CRC Press.
• [産業財産権] Liposome composition for immune induction (2009)
  • 発明者名: Kojima N, Ikehara Y, Tsujimura K
  • 権利者名: Tokai University Educational system, Aichi Prefecture
  • 産業財産権番号: 特許, 11/909,912 (PCT/JP2006/306483)
  • 出願年月日: 2009-05-29
  • 外国
• [産業財産権] Liposome composition for immune induction (2009)
  • 発明者名: Kojima N, Ikehara Y, Tsujimura K
  • 権利者名: Tokai University Educational system, Aichi Prefecture
  • 産業財産権番号: 特許, EA 012618 (PCT/JP2006/306483)
  • 取得年月日: 2009-10-30
  • 外国
• [産業財産権] Liposome composition for immune induction (2008)
  • 発明者名: Kojima N, Ikehara Y, Tsujimura K
  • 権利者名: Tokai University Educational system, Aichi Prefecture
  • 産業財産権番号: 特許, CA 2634038 (PCT/JP2006/306483)
  • 出願年月日: 2008-06-12