粘膜免疫監視の場としてのGALT・NALTを介した免疫制御誘導の解明

• Project/Area Number: 17047009
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: The University of Tokyo
• Principal Investigator: 清野 宏 東京大学, 医科学研究所, 教授 (10271032)
• Project Period (FY): 2005 – 2006
• Project Status: Completed (Fiscal Year 2006)
• Budget Amount: ¥9,900,000 (Direct Cost: ¥9,900,000); Fiscal Year 2006: ¥5,100,000 (Direct Cost: ¥5,100,000); Fiscal Year 2005: ¥4,800,000 (Direct Cost: ¥4,800,000)
• Keywords: 鼻咽腔関連リンパ組織 / バイエル板 / リンフォイドケモカイン / 原基 / 胚中心 / 経鼻ワクチン / 粘膜免疫 / 粘膜ワクチン / AIDSワクチン / 分泌型IgA / 経口ワクチン

Research Abstract

鼻咽腔関連リンパ組織(nasopharynx-associated lymphoid tissue ; NALT)は、腸管におけるパイエル板と同様の粘膜関連リンパ組織の一つである。上気道の免疫監視機構の解明にはNALTの形成メカニズムを明らかにする事が不可欠である。
リンフォイドケモカイン(CXCL13,CCL19,CCL21)は二次リンパ組織の初期形成に必須である。まずNALTの初期形成におけるリンフォイドケモカインの役割について検討した。CXCL13欠損マウス胎生期の腸管にはCD3^-CD4^+CD45^+細胞の集積を認めず、その結果、バイエル板は形成されなかった。ところがCXCL13欠損マウスのNALT原基にはCD3^-CD4^+CD45^+細胞の集積が確認された。CCL19及びCCL21の発現不全マウスであるpltマウスのNALT原基にはコントロールマウスと同等のCD3^-CD4^+CD45^+細胞の集積を認めた。以上の結果からリンフォイドケモカインはNALT初期形成に関与しないことが明らかとなった。
リンフォイドケモカインはリンパ組織構築の成熟化に重要な役割を果たしている。そこで我々はNALT組織構築への関与について検討した。CXCL13欠損マウスでは特にB細胞の遊走が傷害されており、NALTのB細胞領域がほとんど認められなかった。コレラトキシンを用いた経鼻免疫によりコントロールマウスのNALTには胚中心が形成されるが、CXCL13欠損マウスのNALTには胚中心は認められなかった。一方でpltマウスのNALTはT細胞領域の形成不全を認めた。以上の結果から胚中心形成やT/B細胞領域などNALT組織構築の成熟化にはリンフォイドケモカインが必須であることが明らかとなった。
このようにNALTの形成初期から成熟化にかけてリンフォイドケモカイン依存性の変化を示すことができた。

Research Products

• [Journal Article] Therapeutic effects of roxithromycin in interleukin-10-deficient colitis. (2007)
  • Author(s): Tamagawa, H. et al.
  • Journal Title: Inflammatory Bowel Diseases 13・5 Pages: 547-556
• [Journal Article] Intraepithelial lymphocytes : their shared and divergent immunological behaviors in the small and large intestine. (2007)
  • Author(s): Kunisawa, J. et al.
  • Journal Title: Immunological Reviews 215 Pages: 136-153
• [Journal Article] Intranasal immunization with phosphorylcholine induces antigen specific mucosal and systemic immune responses in mice. (2007)
  • Author(s): Tanaka, N. et al.
  • Journal Title: Vaccine 25・14 Pages: 2680-2687
• [Journal Article] Oral feeding of Bifidobacterium bifidum (BGN4) prevents CD4^+ CD45RB^<high> T cell-mediated inflammatory bowel disease by inhibition of disordered T cell activation. (2007)
  • Author(s): Kim, N.et al.
  • Journal Title: Clinical Immunology 123・1 Pages: 30-39
• [Journal Article] Sphingosine 1-phosphate regulates peritoneal B-cell trafficking for subsequent intestinal IgA production. (2007)
  • Author(s): Kunisawa, J, et al.
  • Journal Title: Blood. 109・9 Pages: 3749-3756
• [Journal Article] Gut lymphocyte migration : we are halfway 'home'. (2007)
  • Author(s): McGhee, J.R. et al.
  • Journal Title: Trends in Immunology 28・4 Pages: 150-153
• [Journal Article] Regulatory role of Peyer's patches for the inhibition of OVA-induced allergic diarrhea. (2007)
  • Author(s): Takayama, N. et al.
  • Journal Title: Clinical Immunology 123・2 Pages: 199-208
• [Journal Article] A second generation of double mutant cholera toxin adjuvants : enhanced immunity without intracellular trafficking. (2006)
  • Author(s): Hagiwara, Y. et al.
  • Journal Title: Journal of Immunology 177・5 Pages: 3045-3054
• [Journal Article] Cutting edge : Uniqueness of lymphoid chemokine requirement for the initiation and maturation of nasopharynx-associated lymphoid tissue organogenesis. (2006)
  • Author(s): Fukuyama, S. et al.
  • Journal Title: Journal of Immunology 177・7 Pages: 4276-4280
• [Journal Article] Mucosal vaccine targeting improves onset of mucosal and systemic immunity to botulinum neurotoxin A. (2006)
  • Author(s): Maddaloni, M. et al.
  • Journal Title: Journal of Immunology 177・8 Pages: 5524-5532
• [Journal Article] Innate immunity in the mucosal immune system. (2006)
  • Author(s): Nochi, T. et al.
  • Journal Title: Current Pharmaceutical Design 12・32 Pages: 4203-4213
• [Journal Article] Colitis in mice lacking the common cytokine receptor gamma chain is mediated by IL-6-producing CD4+ T cells. (2005)
  • Author(s): Kai, Y., Takahashi, I., Ishikawa, H., Hiroi, T., Mizushima, T., Matsuda, C., Kishi, D., Hamada, H., Tamagawa, H., Ito, T., Yoshizaki, K., Kishimoto, T., Matsuda, H., Kiyono, H.
  • Journal Title: Gastroenterology. 128 Pages: 922-934
• [Journal Article] Prenatal blockage of lymphotoxin beta receptor and TNF receptor p55 signaling cascade resulted in the acceleration of tissue genesis for isolated lymphoid follicles in the large intestine. (2005)
  • Author(s): Kweon, M.N., Yamamoto, M., Rennert, P.D., Park, E.J., Lee, A.Y., Chang, S.Y., Hiroi, T., Nanno, M., Kiyono, H
  • Journal Title: J.Immunol. 174 Pages: 4365-4372
• [Journal Article] Intestinal gamma delta T cells develop in mice lacking thymus, all lymph nodes, Peyer's patches, and isolated lymphoid follicles. (2005)
  • Author(s): Nonaka, S., Naito, T., Chen, H., Yamamoto, M., Moro, K., Kiyono, H.
  • Journal Title: J.Immunol. 174 Pages: 1906-1912
• [Journal Article] Nasal IL-12p70 DNA prevents and treats intestinal allergic diarrhea. (2005)
  • Author(s): Hino, A., Fukuyama, S., Kataoka, K., Kweon, MN., Fujihashi, K.
  • Journal Title: J.Immunol. 174 Pages: 7423-7432
• [Journal Article] Triggering of TLR3 by polyI:C in human corneal epithelial cells to induce inflammatory cytokines. (2005)
  • Author(s): Ueta, M., Hamuro, J., Kiyono, H., Kinoshita, S.
  • Journal Title: Biochem.Biophys.Res.Commun. 331 Pages: 285-294
• [Journal Article] Nontoxic Shiga toxin derivatives from Escherichia coli possess adjuvant activity for the augmentation of antigen-specific immune responses via dendritic cell activation. (2005)
  • Author(s): Ohmura, M., Yamamoto, M., Tomiyama -Miyaji, C., Yuki, Y., Takeda, Y., Kiyono, H.
  • Journal Title: Infect.Immun. 73 Pages: 4088-4097
• [Journal Article] A rice-based edible vaccine expressing multiple T cell epitopes induces oral tolerance for inhibition of Th-2 mediated IgE responses. (2005)
  • Author(s): Takagi, H., Hiroi, H., Yang, L., Tada, Y., Yuki, Y., Takamura, K., Ishimitsu, R., Kawauchi, H., Kiyono, H., Takaiwa, F.
  • Journal Title: Proc.Nat.Acad.Sci.USA. 102 Pages: 17525-17530
• [Journal Article] Production of a recombinant cholera toxin B subunit-insulin B chain peptide hybrid protein by Brevibacillus choshinensis expression system as a nasal vaccine against autoimmune diabetes. (2005)
  • Author(s): Yuki, Y., Hara-Yakoyama, C., Guadiz, AA., Udak, S., Kiyono, H.
  • Journal Title: Biotechnol.Bioeng. 92 Pages: 803-809
• [Journal Article] A novel neurotoxoid vaccine prevents mucosal botulism. (2005)
  • Author(s): Kobayashi, R., Kohda, T., Kataoka, K., Ihara, H., Kozaki, S., Pascual, DW., Staats, HF., Kiyono, H., McGhee, JR., Fujihashi K.
  • Journal Title: J.Immunol. 174 Pages: 2190-2195
• [Journal Article] A marvel of mucosal T cells and secretory antibodies for the creation of first lines of defense. (2005)
  • Author(s): Kunisawa, J., Kiyono, H.
  • Journal Title: Cell Mol.Life Sci 62 Pages: 1308-1321
• [Journal Article] Mucosa-associated lymphoid tissues in the aerodigestive tract : their shared and divergent traits and their importance to the orchestration of the mucosal immune system. (2005)
  • Author(s): Kunisaw, J., Fukuyama, S., Kiyono, H.
  • Journal Title: Curr.Mol.Med. 5 Pages: 557-572