粘膜免疫と自己識別

2010 Fiscal Year Annual Research Report

• Project Area: Immunological Self Recognition and its Disorders
• Project/Area Number: 19059003
• Research Institution: The University of Tokyo
• Principal Investigator: 清野 宏 東京大学, 医科学研究所, 教授 (10271032)
• Co-Investigator(Kenkyū-buntansha): SIDONIA Fagarasan 独立行政法人理化学研究所, 免疫アレルギー科学総合研究センター, チームリーダー (00391970)
• Keywords: 共生細菌 / パイエル板 / IgA / 絨毛上皮細胞 / 自然免疫担当細胞 / 濾胞性樹状細胞 / レチノイン酸

Research Abstract

平成22年度は、昨年に引き続きパイエル板内共生細菌の同定、およびその細菌による宿主免疫機構の誘導について研究を進めた結果、これまでに、1.マウス小腸パイエル板内にAlcaligenesが恒常的に生息している事、2.Alcaligenesがパイエル板樹状細胞に作用し、IL-6やBAFFといったIgA誘導サイトカイン産生を促すとともにIgA産生B細胞を誘導する事、3.B細胞欠損マウスにおいてパイエル板内Alcaligenesが減少する事、4.高次哺乳類であるカニクイザルおよびヒトのパイエル板内においてもAlcaligenesが検出される事を明らかとした。これらの結果は、「腸内細菌による粘膜組織内共生関係構築」という新規概念を提唱するものとしてPNAS誌に報告された(Proc Natl Acad Sci USA.2010;107:7419-7424.)。一方、絨毛上皮細胞のフコシル化誘導機構の解明を進めた結果、これまでに骨髄由来細胞のうちT細胞やB細胞といった獲得免疫担当細胞の関与は見られないものの、粘膜固有層に存在する自然免疫担当細胞であるCD11陽性細胞、特にマクロファージや好酸球がMyD88分子を介してフコシル化上皮細胞を誘導する事を明らかとした。
分担研究者であるSidonia Fagarasanのグループは、パイエル板濾胞性樹状細胞が腸内細菌とレチノイン酸刺激を受けCXCL13やBAFFを産生する事により、IgA陽性B細胞を誘導する事を明らかとした。本研究結果は、IgA抗体産生におけるパイエル板濾胞性樹状細胞の新たな役割を示しており、粘膜面における抗体産生機構の解明に多大な貢献をするものである。なお本研究成果はImmunity誌に報告された(Immunity.2010 23;33:71-83)。

Research Products

• [Journal Article] Distinct fucosylation of M cells and epithelial cells by Fut1 and Fut2, respectively, in response to intestinal environmental stress. (2011)
  • 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: 822-8
  • Peer Reviewed
• [Journal Article] Peaceful mutualism in the gut : revealing key commensal bacteria for the creation and maintenance of immunological homeostasis. (2011)
  • Author(s): Kunisawa J, Kiyono H.
  • Journal Title: Cell Host Microbe. Volume: 17 Pages: 83-4
  • Peer Reviewed
• [Journal Article] Epithelial cell microRNAs in gut immunity. (2011)
  • Author(s): Goto Y, Kiyono H.
  • Journal Title: Nat Immunol. Volume: 12 Pages: 195-7
  • Peer Reviewed
• [Journal Article] Vitamin A-dependent transcriptional activation of the nuclear factor of activated T cells c1 (NFATc1) is critical for the development and survival of B1 cells. (2011)
  • Author(s): Maruya M, Suzuki K, Fujimoto H, Miyajima M, Kanagawa O, Wakayama T, Fagarasan S
  • Journal Title: Proc Nat1 Acad Sci U S A. Volume: 108 Pages: 722-7
  • 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 U S A. Volume: 107 Pages: 7419-24
  • Peer Reviewed
• [Journal Article] Secretory IgA-mediated protection against V.cholerae 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 U S A. Volume: 107 Pages: 8794-9
  • Peer Reviewed
• [Journal Article] Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines. (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: Nat Mater. Volume: 9 Pages: 572-8
  • Peer Reviewed
• [Journal Article] IL-15 triggers an antiapoptotic pathway in human intraepithelial lymphocytes that is a potential new target in celiac disease-associated inflammation and lymphomagenesis. (2010)
  • Author(s): Malamut G, El Machhour R, Montcuquet N, Martin-Lanneree S, Dusanter-Fourt I, Verkarre V, Mention JJ, Rahmi G, Kiyono H, Butz EA, Brousse N, Cellier C, Cerf-Bensussan N, Meresse B.
  • Journal Title: J Clin Invest. Volume: 120 Pages: 2131-43
  • Peer Reviewed
• [Journal Article] In vivo molecular imaging analysis of a nasal vaccine that induces protective immunity against botulism in nonhuman 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.
  • Journal Title: J Immunol. Volume: 185 Pages: 5436-43
  • Peer Reviewed
• [Journal Article] Mucosal regulatory cells in the gastrointestinal tract and periodontium. (2010)
  • Author(s): Takahashi I, Fujihashi K, Kiyono H.
  • Journal Title: Periodontol Volume: 54 Pages: 247-56
  • Peer Reviewed
• [Journal Article] Interleukin-1 family cytokines as mucosal vaccine adjuvants for induction of protective immunity against influenza virus. (2010)
  • Author(s): Kayamuro H, Yoshioka Y, Abe Y, Arita S, Katayama K, Nomura T, Yoshikawa T, Kubota-Koketsu R, Ikuta K, Okamoto S, Mori Y, Kunisawa J, Kiyono H, Itoh N, Nagano K, Kamada H, Tsutsumi Y, Tsunoda S.
  • Journal Title: J Virol. Volume: 84 Pages: 12703-12
  • Peer Reviewed
• [Journal Article] High affinity of interaction between superantigen and T cell receptor Vbeta molecules induces a high level and prolonged expansion of superantigen-reactive CD4+ T cells. (2010)
  • Author(s): Omoe K, Nunomura W, Kato H, Li ZJ, Igarashi O, Araake M, Sano K, Ono HK, Abe Y, Hu DL, Nakane A, Kiyono H, Takakuwa Y, Shinagawa K, Uchiyama T, Imanishi K.
  • Journal Title: J Biol Chem. Volume: 285 Pages: 30427-35
  • Peer Reviewed
• [Journal Article] Aberrant interaction of the gut immune system with environmental factors in the development of food allergies. (2010)
  • Author(s): Kunisawa J, Kiyono H.
  • Journal Title: Curr Allergy Asthma Rep. Volume: 10 Pages: 215-21
  • Peer Reviewed
• [Journal Article] The sensing of environmental stimuli by follicular dendritic cells promotes immunoglobulin A generation in the gut. (2010)
  • Author(s): Suzuki K, Maruya M, Kawamoto S, Sitnik K, Kitamura H, Agace WW, Fagarasan S.
  • Journal Title: Immunity. Volume: 33 Pages: 71-83
  • Peer Reviewed
• [Journal Article] Adaptive immune regulation in the gut : T cell-dependent and Tcell-independent IgA synthesis. (2010)
  • Author(s): Fagarasan S, Kawamoto S, Kanagawa O, Suzuki K.
  • Journal Title: Annu Rev Immunol Volume: 28 Pages: 243-73
  • Peer Reviewed
• [Journal Article] Advances in Immunology.Mucosal immunity.Preface. (2010)
  • Author(s): Fagarasan S, Cerutti A.
  • Journal Title: Adv Immunol. Volume: 107 Pages: xiii-xiv
  • Peer Reviewed
• [Journal Article] GALT : organization and dynamics leading to IgA synthesis. (2010)
  • Author(s): Suzuki K, Kawamoto S, Maruya M, Fagarasan S.
  • Journal Title: Adv Immunol Volume: 107 Pages: 153-85
  • Peer Reviewed
• [Journal Article] Roles of B-1 and B-2 cells in innate and acquired IgA-mediated immunity. (2010)
  • Author(s): Suzuki K, Maruya M, Kawamoto S, Fagarasan S.
  • Journal Title: Immunol Rev. Volume: 237 Pages: 180-90
  • Peer Reviewed
• [Journal Article] Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation have impaired gut homeostasis and compromised mucosal defense. (2010)
  • Author(s): Wei M, Shinkura R, Doi Y, Maruya M, Fagarasan S, Honjo T.
  • Journal Title: Nat Immunol. Volume: 12 Pages: 264-70
  • Peer Reviewed
• [Presentation] Chaperon-Like Antigen Presentaion by Nanogel-Based Vaccine at Nasal Epithelium (2011)
  • Author(s): HIROSHI KIYONO
  • Organizer: Avison Biomedical Symposium 2011
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2011-02-25
• [Presentation] New Prospects on the Aerodigestive Immunity for Mucosal Vaccine Development (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: Prato Conference on the Pathogenesis of Bacterial Diseases of Animals
  • Place of Presentation: Prato, Italy
  • Year and Date: 2010-10-09
• [Presentation] Mucosal Nanogel-based Chaperon Vaccine for the induction of protective immunity (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: 4^<th> Vaccine and ISV Annuals Global Congress
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2010-10-04
• [Presentation] Intra-Tissue habitation of commensal bacteria in Peyer's patches for gut immunity (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: 8^<th> German-Japanease Symposium, Regulation of immune response and diseases
  • Place of Presentation: Cuxhahen, Germany.
  • Year and Date: 2010-09-27
• [Presentation] Intra-tissue habitation of intestinal opportunistic bacteria in mammalian gut-associated lymphoid tissues for the creation of a mucosal antibody-mediated symiosis (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: 40^<th> Annual Meeting DGFI German Society for Immunology
  • Place of Presentation: Leipzig, Germany
  • Year and Date: 2010-09-26
• [Presentation] Mucosal chaperoning nanogel vaccine for the induction of protective immunity (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: The 10^<th> Awaji International Forum on Infection and Immunity (United states-Japan Cooperative Medical Science Program 23^<rd> Joint Meeting of the AIDS Panels
  • Place of Presentation: Awaji, Japan.淡路夢舞台国際会議場
  • Year and Date: 2010-09-08
• [Presentation] Role of Intestinal Glycosylation for the Mucosal Immne System and Mucosal Vaccine Development (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: 1^<st> Asia Pacific Workshop on Neurovirology Seoul 2010
  • Place of Presentation: Seoul, Korea.
  • Year and Date: 2010-07-16
• [Presentation] Craniofacial Mucosal Immune Sysem : Uniqueness of lymphoid Organogenesis and Immunological Function for NALT and TALT (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: The 7^<th> Intenational Symposium on Tonsils and Mucosal Barriers of the Upper Airways
  • Place of Presentation: Asahikawa, Hokkaido旭川グランドホテル
  • Year and Date: 2010-07-08
• [Presentation] Mucosal Immunity in the Control of Infectious Diseases (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: Pasteur-Areva Course Anti-Viral Imjmunity
  • Place of Presentation: Shanghai, China
  • Year and Date: 2010-05-28
• [Presentation] Basic principals of immune responces : innate versus adaptive immunity (2010)
  • Author(s): HIROSHI KIYONO
  • Organizer: The 10^<th> International Advanced Course on Vaccinology in Asia Pacific Region
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2010-05-10
• [Book] 臨床粘膜免疫学 (2010)
  • Author(s): 清野宏
  • Total Pages: 722
  • Publisher: 株式会社シナジー