Development of the antibody medical treatment to autoimmune and asthmatic diseases based on new target molecule.

2013 Fiscal Year Final Research Report

• Project/Area Number: 23390260
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: 膠原病・アレルギー・感染症内科学
• Research Institution: Juntendo University
• Principal Investigator: OKUMURA Ko 順天堂大学, 医学部, 教授 (50009700)
• Co-Investigator(Kenkyū-buntansha): AKIBA Hisaya 順天堂大学, 医学研究科, 准教授 (60338316) ; KOJIMA Yuko 順天堂大学, 医学研究科, 助教 (60231312)
• Project Period (FY): 2011-04-01 – 2014-03-31
• Keywords: 自己免疫疾患 / 関節リウマチ / 抗体療法 / 喘息

Research Abstract

In this study, we demonstrated a critical contribution of TIM-4 to the development of collagen-induced arthritis (CIA) and collagen antibody-induced arthritis (CAIA), which are well-established animal model for the human rheumatoid arthritis. Administration of anti-TIM-4 mAb significantly inhibited the development of CIA and CAIA with a concomitant decrease of IL-6 and IL-1 beta in the ankle joints. Importantly, high levels of soluble TIM-4 were detected in sera of CIA mice as compared with naive mice. Moreover, soluble TIM-4 stimulation significantly induced IL-6 and TNF-alpha production by macrophages. These effects might be mediated by TIM-4-LMIR5 interaction. It is noteworthy that the inhibitory effects against the development and progression of arthritis by anti-TIM-4 mAb were observed when anti-TIM-4 mAb was administrated after the onset or even after the establishment of arthritis. TIM-4 thus represents a novel target for intervention of rheumatoid arthritis.

Research Products

• [Journal Article] Sphingomyelin and ceramide are physiological ligands for human LMIR3/CD300f, inhibiting FcepsilonRI-mediated mast cell activation (2014)
  • Author(s): Izawa, K., M. Isobe, T. Matsukawa, S. Ito, A. Maehara, M. Takahashi, Y. Yamanishi, A. Kaitani, T. Oki, K. Okumura, T. Kitamura, and J. Kitaura
  • Journal Title: J Allergy Clin Immunol Volume: 133 Pages: 270-273, e271-277
  • DOI: 10.1016/j.jaci.2013.08.008
• [Journal Article] TIM-4 has dual function in the induction and effector phases of murine arthritis (2013)
  • Author(s): Abe, Y., F. Kamachi, T. Kawamoto, F. Makino, J. Ito, Y. Kojima, D. Moustapha Ael, Y. Usui, H. Yagita, Y. Takasaki, K. Okumura, and H. Akiba
  • Journal Title: J Immunol Volume: 191 Pages: 4562-4572
  • DOI: 10.4049/jimmunol.1203035
• [Journal Article] IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation (2013)
  • Author(s): Kamijo, S., H. Takeda, T. Tokura, M. Suzuki, K. Inui, M. Hara, H. Matsuda, A. Matsuda, K. Oboki, T. Ohno, H. Saito, S. Nakae, K. Sudo, H. Suto, S. Ichikawa, H. Ogawa, K. Okumura, and T. Takai
  • Journal Title: J Immunol Volume: 190 Pages: 4489-4499
  • DOI: 10.4049/jimmunol.1201212
• [Journal Article] Transcriptional regulation of the mouse CD11c promoter by AP-1 complex with JunD and Fra2 in dendritic cells (2013)
  • Author(s): Hara, M., H. Yokoyama, K. Fukuyama, N. Kitamura, N. Shimokawa, K. Maeda, S. Kanada, T. Ito, Y. Usui, H. Ogawa, K. Okumura, M. Nishiyama, and C. Nishiyama
  • Journal Title: Mol Immunol Volume: 53 Pages: 295-301
  • DOI: 10.1016/j.molimm.2012.08.004
• [Journal Article] Blockade of CD70-CD27 interaction inhibits induction of allergic lung inflammation in mice (2012)
  • Author(s): Makino, F., J. Ito, Y. Abe, N. Harada, F. Kamachi, H. Yagita, K. Takahashi, K. Okumura, and H. Akiba
  • Journal Title: Am J Respir Cell Mol Biol Volume: 47 Pages: 298-305
  • DOI: 10.1165/rcmb.2011-0354OC
• [Journal Article] The receptor LMIR3 negatively regulates mast cell activation and allergic responses by binding to extracellular ceramide (2012)
  • Author(s): Izawa, K., Y. Yamanishi, A. Maehara, M. Takahashi, M. Isobe, S. Ito, A. Kaitani, T. Matsukawa, T. Matsuoka, F. Nakahara, T. Oki, H. Kiyonari, T. Abe, K. Okumura, T. Kitamura, and J. Kitaura
  • Journal Title: Immunity Volume: 37 Pages: 827-839
  • DOI: 10.1016/j.immuni.2012.08.018
• [Journal Article] Expression pattern changes and function of RANKL during mouse lymph node microarchitecture development (2012)
  • Author(s): Sugiyama, M., G. Nakato, T. Jinnohara, H. Akiba, K. Okumura, H. Ohno, and H. Yoshida
  • Journal Title: Int Immunol Volume: 24 Pages: 369-378
  • DOI: 10.1093/intimm/dxs002
• [Journal Article] Dietary resveratrol prevents the development of food allergy in mice (2012)
  • Author(s): Okada, Y., K. Oh-oka, Y. Nakamura, K. Ishimaru, S. Matsuoka, K. Okumura, H. Ogawa, M. Hisamoto, T. Okuda, and A. Nakao
  • Journal Title: PLoS One Volume: 7 Pages: e44338
  • DOI: 10.1371/journal.pone.0044338
• [Journal Article] Inhibitory receptor paired Ig-like receptor B is exploited by Staphylococcus aureus for virulence (2012)
  • Author(s): Nakayama, M., K. Kurokawa, K. Nakamura, B. L. Lee, K. Sekimizu, H. Kubagawa, K. Hiramatsu, H. Yagita, K. Okumura, T. Takai, D. M. Underhill, A. Aderem, and K. Ogasawara
  • Journal Title: J Immunol Volume: 189 Pages: 5903-5911
  • DOI: 10.4049/jimmunol.1201940
• [Journal Article] Role of PU. 1 in MHC class II expression through transcriptional regulation of class II transactivator pI in dendritic cells (2012)
  • Author(s): Kitamura, N., H. Yokoyama, T. Yashiro, N. Nakano, M. Nishiyama, S. Kanada, T. Fukai, M. Hara, S. Ikeda, H. Ogawa, K. Okumura, and C. Nishiyama
  • Journal Title: J Allergy Clin Immunol Volume: 129 Pages: 814-824, e816
  • DOI: 10.1016/j.jaci.2011.10.019
• [Journal Article] Cyclooxygenase-2 inhibition restores ultraviolet B-induced downregulation of ATP2A2/SERCA2 in keratinocytes : possible therapeutic approach of cyclooxygenase-2 inhibition for treatment of Darier disease (2012)
  • Author(s): Kamijo, M., C. Nishiyama, A. Takagi, N. Nakano, M. Hara, S. Ikeda, K. Okumura, and H. Ogawa
  • Journal Title: Br J Dermatol Volume: 166 Pages: 1017-1022
  • DOI: 10.1111/j.1365-2133.2011.10789.x
• [Journal Article] Involvement of PU. 1 in mast cell/basophil-specific function of the human IL1RL1/ST2 promoter (2012)
  • Author(s): Baba, Y., K. Maeda, T. Yashiro, E. Inage, F. Niyonsaba, M. Hara, R. Suzuki, Y. Ohtsuka, T. Shimizu, H. Ogawa, K. Okumura, and C. Nishiyama
  • Journal Title: Allergol Int Volume: 61 Pages: 461-467
  • DOI: 10.2332/allergolint.12-OA-0424
• [Journal Article] GATA2 is a critical transactivator for the human IL1RL1/ST2 promoter in mast cells/basophils : opposing roles for GATA2 and GATA1 in human IL1RL1/ST2 gene expression (2012)
  • Author(s): Baba, Y., K. Maeda, T. Yashiro, E. Inage, K. Kasakura, R. Suzuki, F. Niyonsaba, M. Hara, A. Tanabe, H. Ogawa, K. Okumura, Y. Ohtsuka, T. Shimizu, and C. Nishiyama
  • Journal Title: J Biol Chem Volume: 287 Pages: 32689-32696
  • DOI: 10.1074/jbc.M112.374876
• [Journal Article] Extracellular double-stranded RNA induces TSLP via an endosomal acidification-and NF-kappaB-dependent pathway in human keratinocytes (2011)
  • Author(s): Vu, A. T., X. Chen, Y. Xie, S. Kamijo, H. Ushio, J. Kawasaki, M. Hara, S. Ikeda, K. Okumura, H. Ogawa, and T. Takai
  • Journal Title: J Invest Dermatol Volume: 131 Pages: 2205-2212
  • DOI: 10.1038/jid.2011.185
• [Journal Article] Crucial role for autophagy in degranulation of mast cells (2011)
  • Author(s): Ushio, H., T. Ueno, Y. Kojima, M. Komatsu, S. Tanaka, A. Yamamoto, Y. Ichimura, J. Ezaki, K. Nishida, S. Komazawa-Sakon, F. Niyonsaba, T. Ishii, T. Yanagawa, E. Kominami, H. Ogawa, K. Okumura, and H. Nakano
  • Journal Title: J Allergy Clin Immunol Volume: 127 Pages: 1267-1276 e1266
  • DOI: 10.1016/j.jaci.2010.12.1078
• [Journal Article] Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation (2011)
  • Author(s): Ohno, T., K. Oboki, H. Morita, N. Kajiwara, K. Arae, S. Tanaka, M. Ikeda, M. Iikura, T. Akiyama, J. Inoue, K. Matsumoto, K. Sudo, M. Azuma, K. Okumura, T. Kamradt, H. Saito, and S. Nakae
  • Journal Title: PLoS One Volume: 6 Pages: e18404
  • DOI: 10.1371/journal.pone.0018404
• [Journal Article] Notch1-mediated signaling induces MHC class II expression through activation of class II transactivator promoter III in mast cells (2011)
  • Author(s): Nakano, N., C. Nishiyama, H. Yagita, A. Koyanagi, H. Ogawa, and K. Okumura
  • Journal Title: J Biol Chem Volume: 286 Pages: 12042-12048
  • DOI: 10.1074/jbc.M110.138966
• [Journal Article] TIM-1 signaling in B cells regulates antibody production (2011)
  • Author(s): Ma, J., Y. Usui, K. Takeda, N. Harada, H. Yagita, K. Okumura, and H. Akiba
  • Journal Title: Biochem Biophys Res Commun Volume: 406 Pages: 223-228
  • DOI: 10.1016/j.bbrc.2011.02.021
• [Journal Article] Anti-T cell immunoglobulin and mucin domain-2 monoclonal antibody exacerbates collagen-induced arthritis by stimulating B cells (2011)
  • Author(s): Kawamoto, T., Y. Abe, J. Ito, F. Makino, Y. Kojima, Y. Usui, J. Ma, S. Morimoto, H. Yagita, K. Okumura, Y. Takasaki, and H. Akiba
  • Journal Title: Arthritis Res Ther Volume: 13 Pages: R47
  • DOI: 10.1186/ar3288
• [Journal Article] Critical role of transcription factor PU. 1 in the expression of CD80 and CD86 on dendritic cells (2011)
  • Author(s): Kanada, S., C. Nishiyama, N. Nakano, R. Suzuki, K. Maeda, M. Hara, N. Kitamura, H. Ogawa, and K. Okumura
  • Journal Title: Blood Volume: 117 Pages: 2211-2222
  • DOI: 10.1182/blood-2010-06-291898
• [Presentation] Anti-TIM-4 mAb ameliorates allergic lung inflammation by inhibiting TIM-4-mediated mast cell stimulation (2013)
  • Author(s): F. Kamachi
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan (Italy)
  • Year and Date: 20130822-27
• [Presentation] IL-33-mediated innate response and adaptive immune cells contribute to maximum responses of protease allergen-induced allergic airway inflammation (2013)
  • Author(s): S. Kamijo
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan (Italy)
  • Year and Date: 20130822-27
• [Presentation] Involvement of transcription factors PU. 1, GATA1 and GATA2 in the expression and function of human FcepsilonRI on mast cells (2013)
  • Author(s): C. Nishiyama
  • Organizer: 15th International Congress of Immunology
  • Place of Presentation: Milan (Italy)
  • Year and Date: 20130822-27
• [Presentation] Anti-TIM-4 mAb ameliorates allergic lung inflammation by inhibiting TIM-4-mediated mast cell stimulation (2012)
  • Author(s): F. Kamachi
  • Organizer: 第41回日本免疫学会学術集会
  • Place of Presentation: 神戸国際会議場
  • Year and Date: 20121205-07
• [Presentation] プロテアーゼアレルゲンによる気道炎症における獲得免疫細胞およびIL-33を介した自然免疫応答の役割 (2012)
  • Author(s): 上條清嗣
  • Organizer: 第62回アレルギー学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 20121129-1201
• [Presentation] ヒトマスト細胞, 好塩基球におけるST2遺伝子の発現調節 (2012)
  • Author(s): 前田啓子
  • Organizer: 第62回アレルギー学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 20121129-1201
• [Presentation] マスト細胞におけるGATA3の機能解析 (2012)
  • Author(s): 八代拓也
  • Organizer: 第62回アレルギー学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 20121129-1201
• [Presentation] CD70-CD27 Interaction Regulates Asthmatic Response in a Murine Model of Asthma (2011)
  • Author(s): F. Makino
  • Organizer: XXII World Allergy Congress
  • Place of Presentation: Cancún Center Convention and Exhibitions (México)
  • Year and Date: 2011-12-05
• [Presentation] TIM-4 has two different functions in mouse models of arthritis (2011)
  • Author(s): Y. ABE
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2011-11-28
• [Presentation] Paracrine IL-33 stimulation enhances lipopolysaccharide-mediated macrophage activation (2011)
  • Author(s): 大野建州
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2011-11-28
• [Presentation] The role of IL-21 receptor in contact hypersensitivity (2011)
  • Author(s): E. SHIMURA
  • Organizer: 第40回日本免疫学会学術集会
  • Place of Presentation: 幕張メッセ
  • Year and Date: 2011-11-27
• [Presentation] IL-33受容体のマスト細胞・好塩基球特異的発現制御機構解明 (2011)
  • Author(s): 馬場洋介
  • Organizer: 第61回日本アレルギー学会秋季学術大会
  • Place of Presentation: グランドプリンスホテル新高輪
  • Year and Date: 2011-11-11
• [Presentation] Contribution of IL-33 to allergic airway inflammation in mice sensitized subcutaneously and challenged intranasally with cysteine protease allergen
  • Author(s): S. Kamijo
• [Presentation] Soluble form of TIM-4 regulates mast cell activation by binding to LMIR5 and TIM-3
  • Author(s): F. Kamachi
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/meneki/home.html
• [Remarks]
  • URL: http://www.juntendo.ac.jp/graduate/laboratory/labo/atopy_center/