Development study of next generation mucosal vaccine by dendritic cell modification

• Project/Area Number: 17K19543
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Research Field: Pathology, Infection/Immunology, and related fields
• Research Institution: Osaka City University (2018); Chiba University (2017)
• Principal Investigator: Uematsu Satoshi 大阪市立大学, 大学院医学研究科, 教授 (50379088)
• Project Period (FY): 2017-06-30 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥6,500,000 (Direct Cost: ¥5,000,000、Indirect Cost: ¥1,500,000); Fiscal Year 2018: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000); Fiscal Year 2017: ¥3,250,000 (Direct Cost: ¥2,500,000、Indirect Cost: ¥750,000)
• Keywords: IgA / 粘膜免疫 / 粘膜ワクチン / 樹状細胞 / igA / 粘膜アジュバント / 次世代粘膜ワクチン / 分泌型IgA / 粘膜樹状細胞

Outline of Final Research Achievements

Intramuscular immunization with CpG-ODN and curdlan as adjuvants induced not only antigen(Ag)-specific systemic responses (eg, IgG and Th1 production), but also Ag-specific SIgA in feces. Oral challenge induced high levels of Ag-specific fecal IgA for over 3 months. In addition, Ag-specific Th1 and Th17 responses were also induced in the gut following boost. The boost effect was also induced in the lung and vagina. When mice were vaccinated with the pneumococcal antigen PspA by this immunization method and PspA was administered to the respiratory tract, it was possible to significantly suppress pneumococcal tissue invasion.

Academic Significance and Societal Importance of the Research Achievements

病原体特異的全身性免疫と粘膜免疫を誘導することができる次世代ワクチンの開発が切望されている。このプライムブースト法は、強力で長期間の抗原特異的粘膜免疫および全身免疫を誘導することができ、革新的な注射用粘膜ハイブリッドワクチン技術である。今後、基剤の変更により、人で使用できる形態になると考えられる。このワクチン法でワクチンをうっておけば、流行が起こる都度、抗原のみを粘膜面に添加することによって、強力な抗原特異的な粘膜免疫応答を惹起でき、感染そのものを予防することが可能となると考える。全く新しい感染症予防法が確立されつつあると考える。

Research Products

• [Journal Article] Gut carbohydrate inhibits GIP secretion via a microbiota/SCFA/FFAR3 pathway (2018)
  • Author(s): Lee Eun-Young、Zhang Xilin、Miyamoto Junki、Kimura Ikuo、Taknaka Tomoaki、Furusawa Kenichi、Jomori Takahito、Fujimoto Kosuke、Uematsu Satoshi、Miki Takashi
  • Journal Title: Journal of Endocrinology Volume: 239 Issue: 3 Pages: 267-276
  • DOI: 10.1530/joe-18-0241
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal CD103(+)CD11b(+)cDC2 Conventional Dendritic Cells Are Required for Primary CD4(+) T and B Cell Responses to Soluble Flagellin. (2018)
  • Author(s): Flores-Langarica A, Cook C, Muller Luda K, Persson EK, Marshall JL, Beristain-Covarrubias N, Yam-Puc JC, Dahlgren M, Persson JJ, Uematsu S, Akira S, Henderson IR, Lindbom BJ, Agace W, Cunningham AF.
  • Journal Title: Front Immunol. Volume: 9 Pages: 2409-2409
  • DOI: 10.3389/fimmu.2018.02409
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Innate immune adaptor TRIF deficiency accelerates disease progression of ALS mice with accumulation of aberrantly activated astrocytes (2018)
  • Author(s): Komine Okiru、Yamashita Hirofumi、Fujimori-Tonou Noriko、Koike Masato、Jin Shijie、Moriwaki Yasuhiro、Endo Fumito、Watanabe Seiji、Uematsu Satoshi、Akira Shizuo、Uchiyama Yasuo、Takahashi Ryosuke、Misawa Hidemi、Yamanaka Koji
  • Journal Title: Cell Death & Differentiation Volume: 印刷中 Issue: 12 Pages: 2130-2146
  • DOI: 10.1038/s41418-018-0098-3
  • Peer Reviewed / Open Access
• [Journal Article] DUSP10 constrains innate IL-33-mediated cytokine production in ST2hi memory-type pathogenic Th2 cells (2018)
  • Author(s): Yamamoto, T., Endo, Y., Onodera, A., Hirahara, K., Asou, H., Nakajima, T., Kanno, T., Ouchi, Y., Uematsu, S., Nishimasu, H., Nureki, O., Tumes, D. J., Shimojo, N., and Nakayama, T.
  • Journal Title: Nature Communications Volume: 9 Issue: 1 Pages: 4231-4231
  • DOI: 10.1038/s41467-018-06468-8
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice. (2018)
  • Author(s): Nishizawa N, Ito Y, Eshima K, Ohkubo H, Kojo K, Inoue T, Raouf J, Jakobsson PJ, Uematsu S, Akira S, Narumiya S, Watanabe M, Majima M.
  • Journal Title: J Hepatol. Volume: S0168-8278(18) Issue: 1 Pages: 30126-30130
  • DOI: 10.1016/j.jhep.2018.02.009
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Effects of long-term intake of a yogurt fermented with Lactobacillus delbrueckii subsp. bulgaricus 2038 and Streptococcus thermophilus 1131 on mice (2018)
  • Author(s): Usui Yuki、Kimura Yasumasa、Satoh Takeshi、Takemura Naoki、Ouchi Yasuo、Ohmiya Hiroko、Kobayashi Kyosuke、Suzuki Hiromi、Koyama Satomi、Hagiwara Satoko、Tanaka Hirotoshi、Imoto Seiya、Eberl G?rard、Asami Yukio、Fujimoto Kosuke、Uematsu Satoshi
  • Journal Title: International Immunology Volume: 30 Issue: 7 Pages: 319-331
  • DOI: 10.1093/intimm/dxy035
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Generation of tumor antigen-specific murine CD8+ T cells with enhanced anti-tumor activity via highly efficient CRISPR/Cas9 genome editing (2018)
  • Author(s): Ouchi Y, Patil A, Tamura Y, Nishimasu H, Negishi A, Paul SK, Takemura N, Satoh T, Kimura Y, Kurachi M, Nureki O, Nakai K, Kiyono H, Uematsu S.
  • Journal Title: International Immunology Volume: 30 Issue: 4 Pages: 141-154
  • DOI: 10.1093/intimm/dxy006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Eosinophil depletion suppresses radiation-induced small intestinal fibrosis. (2018)
  • Author(s): Takemura N, Kurashima Y, Mori Y, Okada K, Ogino T, Osawa H, Matsuno H, Aayam L, Kaneto S, Park EJ, Sato S, Matsunaga K, Tamura Y, Ouchi Y, Kumagai Y, Kobayashi D, Suzuki Y, Yoshioka Y, Nishimura J, Mori M, Ishii KJ, Rothenberg ME, Kiyono H, Akira S, Uematsu S.
  • Journal Title: Sci Transl Med. Volume: -- Issue: 429 Pages: 264-273
  • DOI: 10.1126/scitranslmed.aan0333
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] L, Bannai E, Yoshikawa N, Kimura Y, Satoh T, Uematsu S, Tanaka H, Yamamoto K. Intestinal microbiota link lymphopenia to murine autoimmunity via PD-1(+)CXCR5(-/dim) B-helper T cell induction. (2017)
  • Author(s): Eri T, Kawahata K, Kanzaki T, Imamura M, Michishita K, Akahira L, Bannai E, Yoshikawa N, Kimura Y, Satoh T, Uematsu S, Tanaka H, Yamamoto K.
  • Journal Title: Scientific Reports Volume: 7 Issue: 1 Pages: 1-17
  • DOI: 10.1038/srep46037
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Herpes simplex virus-1 evasion of CD8+ T cell accumulation contributes to viral encephalitis. (2017)
  • Author(s): Koyanagi N, Imai T, Shindo K, Sato A, Fujii W, Ichinohe T, Takemura N, Kakuta S, Uematsu S, Kiyono H, Maruzuru Y, Arii J, Kato A, Kawaguchi Y.
  • Journal Title: J Clin Invest. Volume: 127 Issue: 10 Pages: 3784-3795
  • DOI: 10.1172/jci92931
  • Peer Reviewed / Open Access
• [Journal Article] A Refined Culture System for Human Induced Pluripotent Stem Cell-Derived Intestinal Epithelial Organoids. (2017)
  • Author(s): Takahashi Y, Sato S, Kurashima Y, Yamamoto T, Kurokawa S, Yuki Y, Takemura N, Uematsu S, Lai CY, Otsu M, Matsuno H, Osawa H, Mizushima T, Nishimura J, Hayashi M, Yamaguchi T, Kiyono H.
  • Journal Title: Stem Cell Reports. Volume: -- Issue: 1 Pages: 314-328
  • DOI: 10.1016/j.stemcr.2017.11.004
  • Peer Reviewed / Open Access
• [Presentation] Eosinophil depletion is a potential therapeutic strategy for radiation-induced fibrosis in small intestine (2018)
  • Author(s): Satoshi Uematsu,
  • Organizer: 18th WORLD CONGRESS OF BASIC AND CLINICAL PHARMACOLOGY (WCP2018)
  • Int'l Joint Research / Invited
• [Presentation] 好酸球と筋線維芽細胞の相互作用は、放射線誘導性線維症に必須の役割を果たす (2018)
  • Author(s): 植松智
  • Organizer: 第４２回日本リンパ学会総会
  • Invited
• [Presentation] 腸内ウイルス叢のデータベース構築と新規腸内ウイルスの探索 (2018)
  • Author(s): 藤本康介、井元清哉、植松智
  • Organizer: 第4回日本骨免疫学会
  • Invited
• [Presentation] 強力に全身免疫と粘膜免疫を誘導する革新的な粘膜ワクチンの開発 (2018)
  • Author(s): 植松智
  • Organizer: BIO Tech2018
  • Invited
• [Presentation] 腸内ウイルス叢の解析について (2018)
  • Author(s): 植松智
  • Organizer: 第８３回日本インターフェロンサイトカイン学会
  • Invited
• [Presentation] 腸内細菌叢と加齢 (2018)
  • Author(s): 藤本康介、植松智
  • Organizer: 第15回DIA日本年会
  • Invited
• [Presentation] 腸管におけるウイルス叢の解析 (2018)
  • Author(s): 藤本康介、植松智
  • Organizer: 第49回日本消化吸収学会総会
  • Invited
• [Presentation] Innovative prime-boost vaccine method strongly induces both systemic and mucosal immunity, (2018)
  • Author(s): Kosuke Fujimoto, Satoshi Uematsu
  • Organizer: 第47回日本免疫学会学術集会
• [Presentation] 腸内微生物叢解析の最前線 (2018)
  • Author(s): 植松智
  • Organizer: 第49回日本小児消化管機能研究会
  • Invited
• [Presentation] Prime-boost vaccination with CpG ODN and curdlan strongly induces both systemic and mucosal immunity (2018)
  • Author(s): Naoki Takemura, Satoshi Uematsu
  • Organizer: 第11回次世代アジュバント研究会
• [Presentation] Intestinal dendritic cell and mucosal vaccine development. (2018)
  • Author(s): Naoki Takemura, Satoshi Uematsu
  • Organizer: 第11回次世代アジュバント研究会
  • Invited
• [Presentation] A new prime-boost vaccine method to strongly induce both systemic and mucosal immunity. (2017)
  • Author(s): Naoki Takemura, Satoshi Uematsu.
  • Organizer: Korea-Japan joint meeting on mucosal immunology.
• [Presentation] 腸管樹状細胞と粘膜ワクチンの開発 (2017)
  • Author(s): 植松智
  • Organizer: 第４１回日本リンパ学会学術集会
  • Invited
• [Presentation] 腸管微生物叢解析の最前線 (2017)
  • Author(s): 植松智
  • Organizer: 第24回日本遺伝子診療学会大会
  • Invited
• [Presentation] Intestinal dendritic cell and mucosal vaccine development (2017)
  • Author(s): 植松智
  • Organizer: 第16回淡路島感染症免疫フォーラム
  • Invited
• [Presentation] Role of innate immunity in acute and chronic small intestinal radiation injury (2017)
  • Author(s): Satoshi Uematsu
  • Organizer: The 1st International Workshop on Radiation-induced Stem Cell Injury and Regeneration
  • Int'l Joint Research / Invited
• [Presentation] Innovative prime-boost vaccine method strongly induces both systemic and mucosal immunity (2017)
  • Author(s): Kosuke Fujimoto, Naoki Takemura, Satoshi Uematsu
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research
• [Presentation] Blockade of TLR3 protects mice from lethal radiation-induced gastrointestinal syndrome (2017)
  • Author(s): Naoki Takemura, Satoshi Uematsu
  • Organizer: 5th Annual Meeting of the International Cytokine & Interferon Society
  • Int'l Joint Research
• [Presentation] Gut microorganisms in healthy Japanese subjects (2017)
  • Author(s): Kosuke Fujimoto, Satoshi Uematsu
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Presentation] Prime-boost vaccination with CpG ODN and curdlan strongly induces both systemic and mucosal immunity (2017)
  • Author(s): Naoki Takemura, Satoshi Uematsu
  • Organizer: 第46回日本免疫学会総会・学術集会
• [Book] 医学のあゆみ 3.【自然免疫の最前線】 内因性リガンドによる自然免疫系の活性化 腸管バリア機構と自然免疫 (2018)
  • Author(s): 藤本 康介, 植松 智
  • Total Pages: 5
  • Publisher: 医歯薬出版株式会社
• [Book] 『糖尿病の最新治療』6.腸内細菌からみて (2018)
  • Author(s): 藤本康介, 植松智
  • Total Pages: 5
  • Publisher: フジメディカル出版