ボツリヌス感染症の予防法の確立を目的とした"M細胞標的型食べるワクチン"開発

• Project/Area Number: 08J00507
• Research Category: Grant-in-Aid for JSPS Fellows
• Allocation Type: Single-year Grants
• Section: 国内
• Research Field: Immunology
• Research Institution: The University of Tokyo
• Principal Investigator: 野地 智法 東京大学, 医科学研究所, 特別研究員(SPD)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥9,000,000 (Direct Cost: ¥9,000,000); Fiscal Year 2010: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 2009: ¥3,000,000 (Direct Cost: ¥3,000,000); Fiscal Year 2008: ¥3,000,000 (Direct Cost: ¥3,000,000)
• Keywords: 粘膜免疫 / コメ型ワクチン / トランスレーショナルリサーチ / 粘膜感染症 / 経口ワクチン / コレラ / 粘膜ワクチン / コメ型経口ワクチン

Research Abstract

研究最終年度に当たる今年度は、申請課題であるコメ型ワクチンを完成させるべく、トランスレーショナルリサーチを組み合わせた研究を実施した。具体的には、コメ型ワクチンのヒトでの免疫原性を評価すべく、日本学術振興会特別研究員の規定の下、ヒト化マウス研究の権威である、米国ノースカロライナ大学のJ.Victor Garcia-Martinez博士の研究室に研究留学し、ヒト化マウスの腸管組織におけるヒトの粘膜免疫学の発達に関する評価を行った。その結果、これまで多数報告されているヒト化マウスの中で、Garcia研究室で作成するヒト化マウス(BLTマウス)は、腸管免疫システムが最も発達しているモデル動物であること、そして粘膜免疫システムで最も重要であるIgA産生が、このBLTマウスのみに高頻度で認められることを明らかにし、粘膜ワクチン研究に最も適したモデル動物であることを明らかにすることに成功した(論文準備中)。一方で、2007年度に申請者が開発し報告したコメ型コレラワクチンが、コレラ毒素に対する防御免疫誘導能に加えて、コレラ菌や病原性大腸菌(生菌)に対する防御免疫も誘導可能であることも、実証することに成功した(PNAS,107:8794-8789,2010)。その他、今年度は、安全性に優れた経鼻ワクチン開発にも力を注ぎ、ナノメートルサイズの粒子(ナノゲル)をワクチンデリバリーとして応用したナノゲル型経鼻ワクチンの開発にも成功し、論文として発表した(Nature Materials、9:572-578,2010)。以上の通り、今年度は、計5報の原著論文を発表し、また本研究期間である平成20-22年の3年間を通して、計18報の論文を発表することができた。3年間の本研究により、粘膜ワクチンを実用化するための、研究基盤を構築することができたと考える。

Research Products

• [Journal Article] Nanogel antigenic protein delivery system for adjuvant-free intranasal vaccine. (2010)
  • Author(s): Nochi T, Yuki Y, Takahashi H, Sawada S, Mejima M, Kohda T, Harada N, Kong IG, Sato A, Kataoka N, Tokuhara D, Kurokawa S, Takahashi Y, Tsukada H, Kozaki S, Akiyoshi K, Kiyono H
  • Journal Title: Nature Materials Volume: 9 Pages: 572-578
  • Peer Reviewed
• [Journal Article] In vivo molecular imaging analysis of a nasal vaccine that induces protective immunity against botulism in non-human primates. (2010)
  • Author(s): Yuki Y^*, Nochi T^*, Harada N, Katakai Y, Shibata H, Mejima M, Kohda T, Tokuhara D, Kurokawa S, Takahashi Y, Ono F, Kozaki S, Terao K, Tsukada H, Kiyono H(^*equally contributed)
  • Journal Title: Journal of Immunology Volume: 185 Pages: 5436-5443
  • Peer Reviewed
• [Journal Article] Secretory lgA-mediated protection against V.cholera and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine. (2010)
  • Author(s): Tokuhara D, Yuki Y, Nochi T, Kodama T, Mejima M, Kurokawa S, Takahashi Y, Nanno M, Nakanishi U, Takaiwa F, Honda T, Kiyono H
  • Journal Title: Proc.Natl.Acad.Sci.USA Volume: 107 Pages: 8794-8789
  • Peer Reviewed
• [Journal Article] Distinct fucosylation of M cells and epithelial cells by Fut1 and Fut2, respectively, in response to intestinal environmental stress. (2010)
  • Author(s): Terahara K, Nochi T. Yoshida M, Takahashi Y, Goto Y, Hatai H, Kurokawa S, Jang MH, Kweon MN, Domino SE, Hiroi T, Yuki Y, Tsunetsugu-Yokota Y, Kobayashi K, Kiyono H
  • Journal Title: Biochem.Biophys.Res.Commun. Volume: 404 Pages: 822-828
  • Peer Reviewed
• [Journal Article] Secretory lgA-mediated protection against V. cholera and heat-labile enterotoxin-producing enterotoxigenic Escherichia coli by rice-based vaccine. (2010)
  • Author(s): Kim DY, Sato A, Fukuyama S, Sagara H, Nagatake T, Kong IG, Goda K, Nochi T, Kunisawa J, Sato S, Yokota Y, Lee CH, Kiyono H.
  • Journal Title: Journal of Immunology Volume: 186 Pages: 4253-5262
  • Peer Reviewed
• [Journal Article] Antigen-sampling cells in the salmonid intestinal epithelium (2010)
  • Author(s): Fuglem B, Jirillo E, Bjerkas I, Kiyono H, Nochi T, Yuki Y, Raida M, Fischer U, Koppang EO
  • Journal Title: Dev.Comp.Immunol. (in press)
  • Peer Reviewed
• [Journal Article] Indigenous opportunistic bacteria inhabit mammalian gut-associated lymphoid tissues and share a mucosal antibody-mediated symbiosis (2010)
  • Author(s): Obata T, Goto Y, Kunisawa J, Sato S, Sakamoto M, Setoyama H, Matsuki T, Nonaka K, Shibata N, Gohda M, Kagiyama Y, Nochi T, Yuki Y, Fukuyama Y, Mukai A, Shinzaki S, Fujihashi K, Sasakawa C, Iijima H, Goto M, Umesaki Y, Benno Y, Kiyono H
  • Journal Title: Proc.Natl.Acad.Sci.USA (in press)
  • Peer Reviewed
• [Journal Article] Expression of newly identified secretory CEACAM1^a isoforms in the intestinal epithelium (2009)
  • Author(s): Terahara K, Yoshida M, Taguchi F, Igarashi O, Nochi T, Gotoh Y, Yamamoto T, Tsunetsugu-Yokota Y, Beauchemin N, Kiyono H
  • Journal Title: Biochem.Biophys.Res.Commun. 383 Pages: 340-346
  • Peer Reviewed
• [Journal Article] Oral MucoRice expressing double-mutant cholera toxin A and B subunits induces toxin-specific neutralizing immunity (2009)
  • Author(s): Yuki Y, Tokuhara D, Nochi T, Yasuda H, Mejima M, Kurokawa S, Takahashi Y, Kataoka N, Nakanishi U, Hagiwara Y, Fujihashi K, Takaiwa F, Kiyono H
  • Journal Title: Vaccine 27 Pages: 5982-5988
  • Peer Reviewed
• [Journal Article] RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium (2009)
  • Author(s): Knoop KA, Kumar N, Butler BR, Sakthivel S, Taylor RT, Nochi T, Akiba H, Yagita H, Kiyono H, Williams IR
  • Journal Title: J.Immunol. 183 Pages: 5783-5747
  • Peer Reviewed
• [Journal Article] Localization of fatty acid binding protein of epidermal type common to dendritic cells and presumptive macrophages in Peyer's patches and epithelial M cells of mouse intestine (2009)
  • Author(s): Suzuki R, Nourani MR, Saino-Saito S, Abe H, Nochi T, Kiyono H, Spener F, Kondo H, Owada Y
  • Journal Title: Histochem.Cell Biol. 132 Pages: 577-584
  • Peer Reviewed
• [Journal Article] Id2-, RORγt-, and LTβR-independent initiation of lymphoid organogenesis in ocular immunity (2009)
  • Author(s): Nagatake T, Fukuyama S, Kim DY, Goda K, Igarashi O, Sato S, Nochi T, Sagara H, Yokota Y, Jetten AM, Kaisho T, Akira S, Mimuro H, Sasakawa C, Fukui Y, Fujihashi K, Akiyama T, Inoue JI, Penninger JM, Kunisawa J, Kiyono H
  • Journal Title: J.Exp.Med. 206 Pages: 2351-2364
  • Peer Reviewed
• [Journal Article] A rice-based oral cholera vaccine induces macaque-specific systemic neutralizing Abs but does not influence pre-existing intestinal immunity (2009)
  • Author(s): Nochi T, Yuki Y, Katakai Y, Shibata H, Tokuhara D, Mejima M, Kurokawa S, Takahashi Y, Nakanishi U, Ono F, Mimuro H, Sasakawa C, Takaiwa F, Terao K, Kiyono H
  • Journal Title: J.Immunol. 183 Pages: 6538-6544
  • Peer Reviewed
• [Journal Article] Uptake via Glycoprotein 2 of FimH^+ bacteria by M cells initiates mucosal immune response (2009)
  • Author(s): Hase K, Kawano K, Nochi T, Pontes GS, Fukuda S, Ebisawa M, Kadokura K, Tobe T, Fujimura Y, Kawano S, Nakato G, Kimura S, Murakami T, Iimura, Hamura K, Fukuoka S, Lowe AW, Waguri S, Itoh K, Kiyono H, Ohno H
  • Journal Title: Nature 462 Pages: 226-230
  • Peer Reviewed
• [Journal Article] Immunological commonalities and distinctions between airway and digestive immunity (2008)
  • Author(s): Kunisawa J, Nochi T, Kiyono H.
  • Journal Title: Trends Immunol 29 Pages: 505-513
  • Peer Reviewed
• [Journal Article] Comprehensive Gene Expression Profiling of Payer's Patch M Cells, Villous M-Like Cells, and Intestinal Epithelial Cells (2008)
  • Author(s): Terahara K, Yoshida M, Igarashi O, Nochi T, Pontes GS, Hase K, Ohno H, Kurokawa S, Mejima M, Takayama N, Yuki Y, Lowe
  • Journal Title: J Immunol. 180 Pages: 7840-7846
  • Peer Reviewed
• [Journal Article] A soluble nonglycosylated recombinant infectious hematopoietic necrosis virus (IHNV) G-protein induces IFNs in rainbow trout (Oncorhynchus mykiss) (2008)
  • Author(s): Verjan N, Ooi EL, Nochi T, Kondo H, Hirono I, Aoki T, Kiyono H, Yuki Y.
  • Journal Title: Fish Shellfish Immunol. 25 Pages: 170-180
  • Peer Reviewed
• [Journal Article] Biological characterization of a recombinant Atlantic salmon type I interferon synthesized in Escherichia coli. (2008)
  • Author(s): Ooi EL, Verjan NG, Hirono I, Nochi T, Kondo H, Aoki T, Kiyono H, Yuki Y
  • Journal Title: Fish Shellfish Immunol. 24 Pages: 506-513
  • Peer Reviewed
• [Journal Article] Peyer's patches are required for intestinal IgA responses to Salmonella (2008)
  • Author(s): Hashizume T, Togawa A, Nochi T, Igarashi O, Kweon MN, Kiyono H, Yamamoto M.
  • Journal Title: Infect. Immun. 76 Pages: 927-934
  • Peer Reviewed
• [Presentation] Nanogel antigen delivery system for adjuvant-free intranasal vaccines. (2010)
  • Author(s): Nochi T, Yuki Y, Takahashi H, Sawada S, Mejima M, Kohda T, Harada N, Kataoka N, Kong IG, Sato A, Tokuhara D, Kurokawa S, Takahashi Y, Tsukada H, Kozaki S, Akiyoshi K, Kiyono H.
  • Organizer: American Association of Immunologist 97^<th> Annual Meeting
  • Place of Presentation: Baltimore, USA
• [Presentation] The gateway for enterobacteria in gastrointestinal tract (2009)
  • Author(s): 野地智法, Gemilson Soares Pontes, 長谷耕二, 吉田理人, Anson Lowe, 大野博司, 清野宏
  • Organizer: 日本細菌学会(招待講演)
  • Place of Presentation: 名古屋
• [Presentation] M細胞の免疫生物学的基礎解明とそれを基盤としたM細胞標的型粘膜ワクチン開発 (2008)
  • Author(s): 野地智法, 清野宏
  • Organizer: 日本食品免疫学会(招待講演)
  • Place of Presentation: 東京
• [Presentation] 粘膜ワクチンによる粘膜感染症の予防法の確立 (2008)
  • Author(s): 野地智法, 清野宏
  • Organizer: 日本家畜臨床感染症シンポジウム(招待講演)
  • Place of Presentation: 東京
• [Presentation] A subunit type of botulinum mucosal vaccine effectively induces protective immunity in non-human primates (2008)
  • Author(s): Nochi T, Yuki Y, Mejima M, Ono F, Katakai Y, Kohda T, Kozaki S, Terao K, Kiyono H
  • Organizer: American Association of Immunologist 95th Annual Meeting
  • Place of Presentation: San Diego, USA
• [Presentation] Rice-based oral vaccine : A new global strategy for cold chain & needle free vaccination (2008)
  • Author(s): Nochi T, Yuki Y, Kiyono H
  • Organizer: BioMalaysia 2008 (Invited speaker)
  • Place of Presentation: Kuala Lumpur, Malaysia
• [Presentation] Exploit of nanogel as a novel carrier of mucosal vaccine : Nanogel mucosal vaccine effectively induces protective immunity against botulinum toxin (2008)
  • Author(s): Nochi T, Yuki Y, Mejima M, Kataoka N, Akiyoshi K, Kiyono H
  • Organizer: Vaccine 2nd Global Congress
  • Place of Presentation: Boston, USA
• [Book] 臨床粘膜免疫学:M細胞 (2010)
  • Author(s): 野地智法、清野宏
  • Publisher: シナジー
• [Book] M細胞標的型粘膜ワクチンによる効果的な粘膜感染症に対する予防法の確立 (2008)
  • Author(s): 野地智法, 清野宏
  • Total Pages: 6
  • Publisher: 消化器と免疫No. 44、日本消化器免疫学会
• [Book] 粘膜感染症に対する予防ワクチン開発の最前線-効果的な免疫応答の誘導を可能にしたM細胞標的型粘膜ワクチン- (2008)
  • Author(s): 野地智法, 清野宏
  • Total Pages: 8
  • Publisher: 感染炎症免疫Vol. 38、医薬の門社
• [Book] 粘膜免疫学の基礎解明とそれを応用した粘膜ワクチン開発 (2008)
  • Author(s): 野地智法, 清野宏
  • Total Pages: 5
  • Publisher: 日本家畜臨床感染症研究会誌3巻2号、日本家畜臨床感染症研究会
• [Book] コメ型経口ワクチンによる粘膜感染症の予防法の確立を目指して (2008)
  • Author(s): 野地智法, 幸義和, 清野宏
  • Total Pages: 4
  • Publisher: ファルマシア44巻7号、日本薬学会
• [Book] M細胞を標的とした粘膜関連リンパ組織への効果的な蛋白質の送達技術の開発 (2008)
  • Author(s): 野地智法, 清野宏
  • Total Pages: 5
  • Publisher: Drug Delivery System 23巻5号、日本DDS学会
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/EnMen/index_e.html
• [Remarks]
  • URL: http://www.ims.u-tokyo.ac.jp/EnMen/index_e.html
• [Patent(Industrial Property Rights)] カチオン性ナノゲルを用いる粘膜ワクチン (2008)
  • Inventor(s): 秋吉一成、清野宏、幸義和、野地智法
  • Industrial Property Rights Holder: 国立大学法人東京医科歯科大学
  • Filing Date: 2008-10-31