IL-33とマスト細胞による新しいネガティブフィードバック機構

2010 Fiscal Year Annual Research Report

• Project/Area Number: 21390303
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: 斎藤 博久 独立行政法人国立成育医療研究センター, 研究所, 副所長 (40130166)
• Co-Investigator(Kenkyū-buntansha): 大保木 啓介 独立行政法人国立成育医療研究センター, 免疫アレルギー研究部, 共同研究員 (80415108) ; 中江 進 東京大学, 医科学研究所・フロンティア研究拠点, 特任准教授 (60450409)
• Keywords: マスト細胞 / IL-33 / 制御性T細胞

Research Abstract

IL-33遺伝子欠損マウスの開発が進み、気道炎症を中心とする各種の炎症性モデル疾患での検討により、IL-33遺伝子の生体における機能の多くを明らかにした。具体的には、IL-33が炎症に荷担する疾患モデルは、喘息モデル、DSS誘導性大腸炎モデル、LPS腹腔注射によるエンドトキシンショックモデルの3種であって、多発性硬化症モデル(EAE)、IV型アレルギーモデル(CHS,DTH)、ConA誘導肝炎モデル、STZ投与糖尿病モデル、には関与しなかった。興味深いのは、IL-33遺伝子欠損マウスでの喘息モデルでは野生型マウスと比べて、肺胞洗浄液中の好酸球数が有意に減少するにもかかわらず、血中IgEや肺胞洗浄液中Th2型サイトカイン濃度の有意な低下は認められない点であった。獲得免疫系への影響が低いことが示唆されたため、次に、感作をすることなくプロテアーゼアレルゲンの経鼻吸入のみで気道に炎症を引き起こすモデルを作成し、気道炎症を評価した。予想通り、IL-33遺伝子欠損マウスでは、このモデルにおいても好酸球浸潤が著減しており、IL-33の機能が自然免疫系に強く働きかけることが明らかとなった。
申請者らの見出した新しいTreg増幅系(C33法)で誘導されるTregの分化形質と機能について、C33法によるTreg誘導に、細胞間の接触または液性因子の重要性を確認するため、分離膜を用いた共培養による検討を行った。その結果、Tregの増幅には、マスト細胞とT細胞の接触が必要である事が明らかとなった。

Research Products

• [Journal Article] Four distinct subtypes of non-IgE-mediated gastrointestinal food allergies in neonates and infants, distinguished by their initial symptoms. (2011)
  • Author(s): Nomura I, Morita H, Hosokawa S, Hoshina H, Fukuie T, Watanabe M, Ohtsuka Y, Shoda T, Terada A, Takamasu T, Arai K, Ito Y, Ohya Y, Saito H, Matsumoto K.
  • Journal Title: J Allergy Clin Immunol. Volume: 127(3) Pages: 685-8.e1-8
  • Peer Reviewed
• [Journal Article] Effect of Th1/Th2 cytokine pretreatment on RSV-induced gene expression in airway epithelial cells. (2011)
  • Author(s): Yamada Y, Matsumoto K, Hashimoto N, Saikusa M, Homma T, Yoshihara S, Saito H.
  • Journal Title: Int Arch Allergy Immunol Volume: 154 Pages: 184-194
  • Peer Reviewed
• [Journal Article] Identification of a poly I : C-inducible membrane protein that participates in dendritic cell-mediated natural killer cell activation. (2010)
  • Author(s): Ebihara T, Azuma M, Oshiumi H, Kasamatsu J, Iwabuchi K, Matsumoto K, Saito H, Taniguchi T, Matsumoto M, Seya T.
  • Journal Title: J Exp Med. Volume: 207 Pages: 2675-2687
  • Peer Reviewed
• [Journal Article] IL-33 is a crucial amplifier of innate rather than acquired immunity. (2010)
  • Author(s): Oboki K, Ohno T, Kajiwara N, Arae K, Morita H, Ishii A, Nambu A, Abe T, Kiyonari H, Matsumoto K, Sudo K, Okumura K, Saito H, Nakae S.
  • Journal Title: Proc Natl Acad Sci USA. Volume: 107 Pages: 18581-18586
  • Peer Reviewed
• [Journal Article] IL-33 mediates inflammatory responses in human lung tissue cells. (2010)
  • Author(s): Yagami A, Orihara K, Morita H, Futamura K, Hashimoto N, Matsumoto K, Saito H, Matsuda A.
  • Journal Title: J Immunol. Volume: 185 Pages: 5743-5750
  • Peer Reviewed
• [Journal Article] Overexpression of LEDGF/DFS70 Induces IL-6 via p38 Activation in HaCaT Cells, Similar to that, Seen in the Psoriatic Condition. (2010)
  • Author(s): Takeichi T, Sugiura K, Muro Y, Matsumoto K, Ogawa Y, Futamura K, Kaminuma O, Hashimoto N, Shimoyama Y, Saito H, Tomita Y.
  • Journal Title: J Invest Dermatol. Volume: 130 Pages: 2760-2767
  • Peer Reviewed
• [Journal Article] Defining cell identity by comprehensive gene expression profiling. (2010)
  • Author(s): Toyoda M, Hamatani T, Okada H, Matsumoto K, Saito H, Umezawa A.
  • Journal Title: Curr Med Chem Volume: 17 Pages: 3245-3252
  • Peer Reviewed
• [Journal Article] Proactive treatment appears to decrease serum IgE levels in patients with severe atopie dermatitis. (2010)
  • Author(s): Fukuie T, Nomura I, Horimukai K, Futamura M, Narita M, Ohzeki T, Matsumoto K, Saito H, Ohya Y.
  • Journal Title: Br J Dermatol. Volume: 163 Pages: 1127-1129
  • Peer Reviewed
• [Journal Article] Analysis of signal transduction pathways involved in anti-CD30 mAb-induced human eosinophil apoptosis. (2010)
  • Author(s): Matsumoto K, Terakawa M, Fukuda S, Saito H.
  • Journal Title: Int Arch Allergy Immunol Volume: 152 Suppl 1:2-8
  • Peer Reviewed
• [Journal Article] Activation of human mast cells through the platelet-activating factor receptor. (2010)
  • Author(s): Kajiwara N, Sasaki T, Bradding P, Cruse G, Sagara H, Ohmori K, Saito H, Ra C, Okayama Y.
  • Journal Title: J Allergy Clin Immunol Volume: 125 Pages: 11137-1145.e6
  • Peer Reviewed
• [Journal Article] Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. (2010)
  • Author(s): Niyonsaba F, Ushio H, Hara M, Yokoi H, Tominaga M, Takamori K, Kajiwara N, Saito H, Nagaoka I, Ogawa H, Okumura K.
  • Journal Title: J Immunol. Volume: 184 Pages: 3526-3534
  • Peer Reviewed
• [Journal Article] Cells of extraembryonic mesodermal origin confer human dystrophin in the mdx model of Duchenne muscular dystrophy. (2010)
  • Author(s): Kawamichi Y, Cui CH, Toyoda M, Makino H, Horie A, Takahashi Y, Matsumoto K, Saito H, Ohta H, Saito K, Umezawa A.
  • Journal Title: J Cell Physiol. Volume: 223 Pages: 695-702
  • Peer Reviewed
• [Journal Article] Phosphodiesterase 4B is essential for T(h)2-cell function and development of airway hyperresponsiveness in allergic asthma. (2010)
  • Author(s): Jin SL, Goya S, Nakae S, Wang D.Bruss M, Hou C, Umetsu D, Conti M.
  • Journal Title: J Allergy Clin Immunol. Volume: 126 Pages: 1252-1259.e12
  • Peer Reviewed
• [Journal Article] Altered effector CD4+ T cell function in IL-21R-/-CD4+ T cell-mediated graft-versus-host disease. (2010)
  • Author(s): Oh I, Ozaki K, Meguro A, Hatanaka K, Kadowaki M, Matsu H, Tatara R, Sato K, Iwakura Y, Nakae S, Sudo K, Teshima T, Leonard WJ, Ozawa K.
  • Journal Title: J Immunol Volume: 185 Pages: 1920-1926
  • Peer Reviewed
• [Journal Article] Amphiregulin is not essential for ovalbumin-induced acute airway inflammation in mice. (2010)
  • Author(s): Kajiwara N, Oboki K, Ohno T, Ishii A, Sunnarborg SW, Okumura K, Saito H, Nakae S.
  • Journal Title: Allergol Int. Volume: 59 Pages: 207-211
  • Peer Reviewed
• [Journal Article] IL-33 and IL-33 receptors in host defense and diseases. (2010)
  • Author(s): Oboki K, Ohno T, Kajiwara N, Saito H, Nakae S.
  • Journal Title: Allergol Int Volume: 59 Pages: 143-160
  • Peer Reviewed
• [Journal Article] IL-1 and Allergy. (2010)
  • Author(s): Nambu A, Nakae S.
  • Journal Title: Allergol Int. Volume: 59 Pages: 125-135
  • Peer Reviewed
• [Journal Article] TNF, but not IL-6 and IL-17, is crucial for the development of T cell-independent psoriasis-like dermatitis in Il1rn-/-mice. (2010)
  • Author(s): Nakajima A, Matsuki T, Komine M, Asahina A, Horai R, Nakae S, Ishigame H, Kakuta S, Saijo S, Iwakura Y.
  • Journal Title: J Immunol. Volume: 185 Pages: 1887-1893
  • Peer Reviewed
• [Journal Article] The role of recipient mast cells in acute and chronic cardiac allo graft rejection in C57BL/6-KitW-sh/W-sh mice. (2010)
  • Author(s): Itoh S, Nakae S, Velotta JB, Kosuge H, Connolly A, Tsai M, Adachi H, Galli SJ, Robbins RC, Fischbein MP.
  • Journal Title: J Heart Lung Transplant Volume: 29 Pages: 401-409
  • Peer Reviewed
• [Journal Article] Essential role of IL-17A in the formation of a mycobacterial infection-induced granuloma in the lung. (2010)
  • Author(s): Okamoto Yoshida Y, Umemura M, Yahagi A, O'Brien RL, Ikuta K, Kishihara K, Hara H, Nakae S, Iwakura Y, Matsuzaki G.
  • Journal Title: J Immunol. Volume: 184 Pages: 4414-4422
  • Peer Reviewed
• [Journal Article] IL-17 contributes to the development of chronic rejection in a murine heart transplant model (2010)
  • Author(s): Itoh S, Nakae S, Axtell RC, Velotta JB, Kimura N, Kajiwara N, Iwakura Y, Saito H, Adachi H, Steinman L, Robbins RC, Fischbein MP.
  • Journal Title: J Clin Immunol. Volume: 30 Pages: 235-240
  • Peer Reviewed
• [Journal Article] Development of IL-17-mediated Delayed-Type Hypersensitivity Is Not Affected by Down-Regulation of IL-25 Expression. (2010)
  • Author(s): Ishii A, Oboki K, Nambu A, Morita H, Ohno T, Kajiwara N, Arae K, Sudo H, Okumura K, Saito H, Nakae S.
  • Journal Title: Allergol Int. Volume: 59 Pages: 1-20
  • Peer Reviewed