CD91に対する分子標的ワクチンによる結核の制御

2007 Fiscal Year Annual Research Report

• Project/Area Number: 19659109
• Research Institution: Hamamatsu University School of Medicine
• Principal Investigator: 小出 幸夫 Hamamatsu University School of Medicine, 医学部, 教授 (30126809)
• Co-Investigator(Kenkyū-buntansha): 永田 年 浜松医科大学, 医学部, 教授 (90275024) ; 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) ; セルバンテス ホルヘ 浜松医科大学, 医学部, 特任研究員 (60377752)
• Keywords: 結核 / 融合蛋白ワクチン / CD91 / 樹状細胞

Research Abstract

結核に対する感染防御免疫としては,CD4+T細胞のみならずCD8+T細胞も重要な働きをしていることが知られている。これらのT細胞の感作には抗原提示細胞として,樹状細胞(DC)が重要な役割を果たす。特に,CD8+T細胞の感作にはcross-primingを行うDCが必須である。そこで,我々はDCに効率よく結核菌の防御抗原が取り込まれる「DCを標的とした新規抗結核ワクチン」の研究を行った。DCの標的分子としてCD91を用いた。これらの分子のリガンドと防御抗原の融合タンパクを作製し,分子標的ワクチンとした。そのリガンドとしては1)結核菌由来HSP70と2)Thrombospodin-1(TSP-1)のヘパリン結合ドメイン(HBD)を用いた。[結果]作製した3種の融合タンパクワクチンは何れもDCに結合することを,コンフォーカル顕微鏡で確認した。1)MPT51はBALB/cマウスに特異的CD8+T細胞を,C57BL/6マウスに特異的CD4+T細胞を誘導できるが,上記2種の融合タンパクを発現するDNAワクチンは何れもMPT51単独よりも顕著に多くの特異的T細胞を誘導できた。2)TSP-1のHBDは主量体を形成してCD91に結合するため,S-S結合の部位まで含める必要があった。3)HSP70をN末のATPase領域とC末のペプチド結合領域に分けて検討した。その結果,C末側たCD91との親和性が認められた。4)同様に,強力な細胞障害性T細胞を誘導できることがin vitro,in vivoで確認できた。

Research Products

• [Journal Article] Intracytoso licListeria monocytogenes induces cell death through caspase-1 activation in murine macrophages (2008)
  • Author(s): Cervantes J, Nagata T, Uchijima M, Shibata K, Koide Y
  • Journal Title: Cell Microbiol 10 Pages: 41-52
  • Peer Reviewed
• [Journal Article] Identification of HLA-A*0201-restricted T-cell epitope on MPT51 protein,a major secreted proteinderived from Mycobacterium tuberculosis,using combination of MPT510verlapping peptide library and computer algorithms (2008)
  • Author(s): Aoshi T, Nagata T, Suzuki M, Hashimoto D, Refiei A, Suda T, ChidaK, Koide Y
  • Journal Title: Infect Immun
  • Peer Reviewed
• [Journal Article] Chemokine receptor-mediated delivery of mycobacterial MPT51 protein efficiently induces antigen-specific T-cell responses (2008)
  • Author(s): Uchijima M, Nagata T, Koide Y.
  • Journal Title: Vaccine (印刷中)
  • Peer Reviewed
• [Journal Article] ntratracheal administration of third-generation lentivirus vector encoding MPT51 from Mycobcaterium tuberculosis induces specific CD8+T-cell responses in the lung (2008)
  • Author(s): Hashimoto D, Nagata T, Uchijima M, Seto S, Suda T, Chida, K, Miyoshi H, Nakamura H, Koide Y
  • Journal Title: Vaccine
  • Peer Reviewed
• [Journal Article] In vivo hierarchy of individual T-cell epitope-specific helper T-cellsubset against anintracellular bacterium (2008)
  • Author(s): Nagata T, Aoshi T, Uchijima M, Koide Y
  • Journal Title: Vaccine
  • Peer Reviewed
• [Journal Article] Effective induction of anti-tumor immune responses with oligomannose-coated liposome targeting to intraperitoneal phagocytic cells (2008)
  • Author(s): 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
  • Journal Title: Cancer Letters 260 Pages: 137-145
  • Peer Reviewed
• [Journal Article] Immunization with dendritic cells loaded with α-galactosylceramide at priming phase,but not at boosting phase,enhances cytotoxic T-lymphocyte activity against infection of intracellular bacteria (2007)
  • Author(s): Enomoto N, Nagata T, Suda T, Uchijima M, Nakamura Y, Kingo C, Nakamura H, Koide Y
  • Journal Title: FEMS Immunol Med Microbiol 51 Pages: 350-362
  • Peer Reviewed
• [Presentation] DNAワクチンを用いた結核菌腫瘍分泌蛋白MPT51のHLA-DR4拘束性CD4+T細胞エピトープの同定 (2008)
  • Author(s): 王 麗欣、永田 年、小出 幸夫
  • Organizer: 第81回日本細菌学会総会
  • Place of Presentation: 京都
  • Year and Date: 20080324-26
• [Presentation] DNAワクチンを用いた結核菌低分子:量分泌蛋白のマウスT細胞エピトープの同定 (2008)
  • Author(s): 鈴木 大介、永田 年、小出 幸夫
  • Organizer: 第81回日本細菌学会総会
  • Place of Presentation: 京都
  • Year and Date: 20080324-26
• [Presentation] MIP-la融合型DNAワクチンは抗原特異的CD8+およびCD4+T細胞の誘導を増強する (2008)
  • Author(s): 内嶋 雅人、永田 年、瀬戸 真太郎、小出 幸夫
  • Organizer: 第81回日本細菌学会総会
  • Place of Presentation: 京都
  • Year and Date: 20080324-26
• [Presentation] Immunization with dentritic cells loaded with a-galactosylceramide, a ligand of NKT cells,at priming phase,but not at boosying phase,enhances cytotoxic T lymphocyte activity against infection by yntracellular bacteria. (2008)
  • Author(s): Enomoto N, Nagata T, Koide Y
  • Organizer: Keystone Symposia
  • Place of Presentation: Keystone, Colorado
  • Year and Date: 20080224-29
• [Presentation] Nucear changes associated with cell death of Listeria monocytogenes-infected macrophages (2007)
  • Author(s): Cervantes J, Nagata T, Uchijima M, Koide Y
  • Organizer: 第37回目本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20071120-22
• [Presentation] Genetic fusion of MIP-lα to a mycobacterial MPT51 antigenenhances the antigen-specific CD8+ T-and CD4+ T-cell responses (2007)
  • Author(s): Uchijima M, Nagata T, ShibataK, Koide Y
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20071120-22
• [Presentation] Characterization of human HLA-DR4-restricted CD4+ T-cell epitope on MPT51 protei, a major secreted protein derived from Mycobacterium tuberculosis (2007)
  • Author(s): Wang L-M, Nagata T, Koide Y
  • Organizer: 第37回日本免疫学会総会・学術集会
  • Place of Presentation: 東京
  • Year and Date: 20071120-22
• [Presentation] 結核菌感染マクロファージにおける膜小胞輸送機構のイメージ解析 (2007)
  • Author(s): 瀬戸 真太郎、小出 幸夫
  • Organizer: 第90回日本細菌学会関東支部総会
  • Place of Presentation: 東京
  • Year and Date: 20071012-13
• [Presentation] Live Mycobacterium tuberculosis blocks phagosome-lusosomefusion by dissociation of late endosomal protein, Rab 7,from phagosome in macrophages (2007)
  • Author(s): Seto S, Koide Y
  • Organizer: The 42th US-Japan conference of .tuberculosis and leprosy
  • Place of Presentation: Zhengzhou ,Henan, China
  • Year and Date: 20070911-14
• [Presentation] In vivo heterogeneity of individual T-cell epitope-specific helper Tcells against an intracellular bacterium (2007)
  • Author(s): Nagata T, Aoshi T, UchijimaM, Koide Y
  • Organizer: DNA Vaccine 2007
  • Place of Presentation: Malaga, Spain
  • Year and Date: 20070523-25
• [Presentation] Chemokine receptor-mediated delivery of mycobacterial MPT51 efficently induces antigen specific T-cell responses (2007)
  • Author(s): Uchijima M, Nagata T, Koide Y
  • Organizer: DNA Vaccine 2007
  • Place of Presentation: Malaga, Spain
  • Year and Date: 20070523-25
• [Presentation] Intratracheal administration of an alternative genetic vaccine, third-generation lentivirus vector encoding MPT51 from Mycobacterium tuberculosis, induces lung-homing specific T-cells. (2007)
  • Author(s): Koide, Y, Hashimoto, D, Uchijima, M, Suda, T, Chida, K, Nagata, T
  • Organizer: DNAVaccine2007
  • Place of Presentation: Malaga, Spain
  • Year and Date: 20070523-25
• [Presentation] Intracellular administration of third-generation lelltivirrus vectors encoding MPT51 from Mycobacterium tuberculosis induces specific T-cell responses in the lung (2007)
  • Author(s): Hashimoto D, Nagata T, Suda T, Chida K, Koide Y
  • Organizer: American Thoracic Society
  • Place of Presentation: San Francisco, USA
  • Year and Date: 20070518-23
• [Presentation] 結核菌感染マクロファージにおけるRabタンパク質局在の網羅的イメージ解析 (2007)
  • Author(s): 瀬戸 真太郎、小出 幸夫
  • Organizer: 第81回日本細菌学会総会
  • Place of Presentation: 京都
  • Year and Date: 20070324-26
• [Presentation] Imaging analysis of intracellular bacteria with host cells (2007)
  • Author(s): Koide Y
  • Organizer: Kyunpook-Hamamatsu Joint Medical Symposium
  • Place of Presentation: Korea
  • Year and Date: 2007-12-07
• [Book] 化学療法の領域 (2007)
  • Author(s): 小出 幸夫
  • Total Pages: 164
  • Publisher: 医薬ジャーナル社