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

2009 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 National Research Institute for Child Health and Development, 免疫アレルギー研究部, 部長 (40130166)
• Co-Investigator(Kenkyū-buntansha): 大保木 啓介 国立成育医療センター(研究所), 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

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、できるだけ多くのマーカーの確認と機能検証を行い、炎症抑制機能のバリデーションを行った。分化形質マーカーとして、Treg機能分子として知られるGITR、CTLA-4、IL-10、FR4の発現を蛍光標識抗体とフローサイトメトリーにより確認した。機能の検証として、TregによるエフェクターT細胞のCD3架橋刺激時増殖に対する抑制活性評価を行った。さらに中和抗体及び遺伝子組換えマウス由来の細胞を用いて、C33法でのTreg誘導を正負に制御する因子の同定を開始した。また、研究材料として必要と考えられるIL-33遺伝子欠損マウスの作成が進捗した。
in vitro Treg誘導系として最も多くの研究がある抗原提示細胞とCD4+T細胞の共培養系との比較をベースとして実験を進め、一般的に重要であるとされる因子は、MHC II、T細胞受容体、副刺激分子、TGF-b1、IL-2であるので、C33法から得られるTreg誘導因子の探索のため、まず、MHC II、マスト細胞に発現する副刺激分子、TGF-b1、IL-2について、その中和抗体や遺伝子欠損マウスを用いて特定の分子機能を欠損した細胞を使用し、C33法でのTreg誘導への影響について検討を加えた。加えて、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開始した。

Research Products

• [Journal Article] beta(2)-Adrenoceptor Agonists Enhance Cytokine-Induced Release of Thymic Stromal Lymphopoietin by Lung Tissue Cells (2010)
  • Author(s): Futamura K, Orihara K, Hashimoto N, Morita H, Fukuda S, Sagara H, Matsumoto K, Tomita Y, Saito H, Matsuda A.
  • Journal Title: Int Arch Allergy Immunol. 152 Pages: 353-61
  • 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. 30 Pages: 235-40
  • Peer Reviewed
• [Journal Article] IQGAP1 and vimentin are key regulator genes in naturally occurring hepatotumorigenesis induced by oxidative stress (2010)
  • Author(s): Tsubota A, Matsumoto K, Mogushi K, Nariai K, Namiki Y, Hoshina S, Hano H, Tanaka H, Saito H, Tada N.
  • Journal Title: Carcinogenesis 31 Pages: 504-11
  • Peer Reviewed
• [Journal Article] Caspase-1, caspase-8, and calpain are dispensable for IL-33 release by macrophages (2009)
  • Author(s): Ohno T, Oboki K, Kajiwara N, Morii E, Aozasa K, Flavell RA, Okumura K, Saito H, Nakae S.
  • Journal Title: J Immunol. 183 Pages: 7890-7
  • Peer Reviewed
• [Journal Article] Tissue remodeling induced by hypersecreted epidermal growth factor and amphiregulin in the airway after an acute asthma attack (2009)
  • Author(s): Enomoto Y, Orihara K, Takamasu T, Matsuda A, Gon Y, Saito H, Ra C, Okayama Y.
  • Journal Title: J Allergy Clin Immunol. 124 Pages: 913-20
  • Peer Reviewed
• [Journal Article] Corneal and conjunctival fibroblasts are major sources of eosinophil-recruiting chemokines (2009)
  • Author(s): Fukagawa K, Okada N, Fujishima H, Nakajima T, Takano Y, Tanaka M, Dogru M, Satake Y, Tsubota K, Saito H.
  • Journal Title: Allergol Int. 58 Pages: 499-508
  • Peer Reviewed
• [Journal Article] Shortening of human cell life span by induction of p16ink4a through the platelet-derived growth factor receptor beta (2009)
  • Author(s): Takahashi H, Toyoda M, Birumachi J, Horie A, Uyama T, Miyado K, Matsumoto K, Saito H, Umezawa A.
  • Journal Title: J Cell Physiol. 221 Pages: 335-42
  • Peer Reviewed
• [Journal Article] Mesenchymal to embryonic incomplete transition of human cells by chimeric OCT4/3(POU5F1)with physiological co-activator EWS (2009)
  • Author(s): Makino H, Toyoda M, Matsumoto K, Saito H, Nishino K, Fukawatase Y, Machida M, Akutsu H, Uyama T, Miyagawa Y, Okita H, Kiyokawa N, Fujino T, Ishikawa Y, Nakamura T, Umezawa A.
  • Journal Title: Exp Cell Res. 315 Pages: 2727-40
  • Peer Reviewed
• [Journal Article] Essentials for starting a pediatric clinical study(2): Role of environment and immunity in the development of childhood allergic and immunologic disorders (2009)
  • Author(s): Saito H.
  • Journal Title: J Toxicol Sci. 34 Pages: Suppl 2:SP313-9
  • Peer Reviewed
• [Journal Article] Polyclonal IgE induces mast cell survival and cytokine production (2009)
  • Author(s): Kashiwakura J, Kawakami Y, Yuki K, Zajonc DM, Hasegawa S, Tomimori Y, Caplan B, Saito H, Furue M, Oettgen HC, Okayama Y, Kawakami T.
  • Journal Title: Allergol Int. 58 Pages: 411-9
  • Peer Reviewed
• [Journal Article] TH2 cytokines potently induce an appetite-stimulating peptide, melanin-concentrating hormone, in human vascular endothelial cells (2009)
  • Author(s): Orihara K, Morita H, Yagami A, Kajiwara N, Nakae S, Matsumoto K, Nagasaki H, Saito Y, Saito H, Matsuda A.
  • Journal Title: J Allergy Clin Immunol. 124 Pages: 612-4, 614.e1-2
  • Peer Reviewed
• [Journal Article] Amphiregulin production by human eosinophils (2009)
  • Author(s): Matsumoto K, Fukuda S, Nakamura Y, Saito H.
  • Journal Title: Int Arch Allergy Immunol. 149 Suppl 1 Pages: 39-44
  • Peer Reviewed
• [Journal Article] Hev B 6.02 is the most important allergen in health care workers sensitized occupationally by natural rubber latex gloves (2009)
  • Author(s): Yagami A, Suzuki K, Saito H, Matsunaga K.
  • Journal Title: Allergol Int. 58 Pages: 347-55
  • Peer Reviewed
• [Journal Article] Dexamethasone and FK506 inhibit expression of distinct subsets of the mokines in human mast cells (2009)
  • Author(s): Kato A, Chustz RT, Ogasawara T, Kulka M, Saito H, Schleimer RP, Matsumoto K.
  • Journal Title: J Immunol. 182 Pages: 7233-43
  • Peer Reviewed
• [Journal Article] Zinc transporter Znt5/Slc30a5 is required for the mast cell-mediated delayed-type allergic reaction but not the immediate-type reaction (2009)
  • Author(s): Nishida K, Hasegawa A, Nakae S, Oboki K, Saito H, Yamasaki S, Hirano T.
  • Journal Title: J Exp Med. 206 Pages: 1351-64
  • Peer Reviewed
• [Journal Article] Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients (2009)
  • Author(s): Takahashi N, Matsumoto K, Saito H, Nanki T, Miyasaka N, Kobata T, Azuma M, Lee SK, Mizutani S, Morio T.
  • Journal Title: J Immunol. 182 Pages: 5515-27
  • Peer Reviewed
• [Journal Article] Intra-articular Injected synovial stem cells differentiate into meniscal cells directly and promote meniscal regeneration without mobilization to distant organs in rat massive meniscal defect (2009)
  • Author(s): Horie M, Sekiya I, Muneta T, Ichinose S, Matsumoto K, Saito H, Murakami T, Kobayashi E.
  • Journal Title: Stem Cells. 27 Pages: 878-87
  • Peer Reviewed