Development of immunotherapy for DNAM-1 as a molecular target in graft-versus-host disease

• Project/Area Number: 19390257
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: SHIBUYA Akira University of Tsukuba, 大学院・人間総合科学研究科, 教授 (80216027)
• Project Period (FY): 2007 – 2008
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥18,720,000 (Direct Cost: ¥14,400,000、Indirect Cost: ¥4,320,000); Fiscal Year 2008: ¥8,840,000 (Direct Cost: ¥6,800,000、Indirect Cost: ¥2,040,000); Fiscal Year 2007: ¥9,880,000 (Direct Cost: ¥7,600,000、Indirect Cost: ¥2,280,000)
• Keywords: 移植片対宿主病 / 同種造血幹細胞移植 / DNAM-1 / 分子標的療法 / CD226 / 骨髄移植

Research Abstract

本研究では申請者らが同定したDNAM-1(CD226)を分子標的としたGVHDに対する新しい診断と免疫療法の基盤開発を行なうことを目的とした。
DNAM-1遺伝子欠損マウスでは野生型に比較し、有意にGVHDの重症度が低く、生存期間が延長した。さらに野生型マウスをドナー細胞としたGVHDモデルマウスにあらかじめDNAM-1に対する中和抗体(TX42)を投与することによって、急性GVHDの発症が抑制されることを明らかにした。これらの結果から、DNAM-1を用いた分子標的療法の可能性が示唆された。

Research Products

• [Journal Article] NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo (2009)
  • Author(s): Lakshmikanth T, Karre K, Shibuya A, Carbone E, Colucci F. et.al.(25人中23番目)
  • Journal Title: J Clin Invest 119 Pages: 1251-63
  • Peer Reviewed
• [Journal Article] Receptor-mediated recognition of melanoma by natural killer cells and its implications for immunotherapy. (2009)
  • Author(s): Lakshmikanth T et. al.
  • Journal Title: The Journal of Clinical Investigation 119 Pages: 1251-1263
  • Peer Reviewed
• [Journal Article] Brief Definitive Report. Accelerated tumor growth in mice deficient in DNAM-1 receptor (2008)
  • Author(s): Iguchi-Manaka A, Kai H, Shibuya A. et.al.(10人中最終著者)
  • Journal Title: J Exp Med 205 Pages: 2959-2964
  • Peer Reviewed
• [Journal Article] Identification of the Fcα/μR isoform specifically expressed in the kidney tubule (2008)
  • Author(s): Kurita N, Honda S, Tahara-Hanaoka S, Shibuya K, Shibuya A. et.al.(8人中最終著者)
  • Journal Title: Mol Immunol 46 Pages: 749-753
  • NAID: 120007138354
  • Peer Reviewed
• [Journal Article] Activation of neutrophils by a novel triggering immunoglobulin-like receptor MAIR-IV (2008)
  • Author(s): Nakano T, Honda S-I, Shibuya K, Shibuya A. et.al.(8人中最終著者)
  • Journal Title: Mol Immunol 45 Pages: 289-294
  • NAID: 120007139098
  • Peer Reviewed
• [Journal Article] Caspase-independent cell death by CD300LF (MAIR-V), an inhibitory immunoglobulin-like receptor on myeloid cells (2008)
  • Author(s): Can I, Tahara-Hanaoka S, Shibuya A. et.al.(9人中最終著者)
  • Journal Title: J Immunol 180 Pages: 207-213
  • Peer Reviewed
• [Journal Article] LFA-1 decreases the antigen dose for T cell activation in vivo (2008)
  • Author(s): Wang Y, Shibuya A. et.al.(11人中最終著者)
  • Journal Title: Int Immunol 20 Pages: 1119-1127
  • NAID: 10022599219
  • Peer Reviewed
• [Journal Article] Accelerated tumor growth in mice deficient in DNAM-1 receptor. (2008)
  • Author(s): Iguchi-Manaka A et. al.
  • Journal Title: The Journal of Experimental Medicine 205 Pages: 2959-2964
  • Peer Reviewed
• [Journal Article] Identification of the Fcα/μR isoform specifically expressed in the kidney tubule (2008)
  • Author(s): Kurita N et. al.
  • Journal Title: Molecular Immunology 46 Pages: 749-753
  • Peer Reviewed
• [Journal Article] Activation of neutrophils by a novel triggering immunoglobulin-like receptor MAIR-IV. (2008)
  • Author(s): Nakano T et. al.
  • Journal Title: Molecular Immunology 45 Pages: 287-294
  • Peer Reviewed
• [Journal Article] Caspase-independent cell death by CD300LF (MAIR-V), an inhibitory mmunoglobulin-like receptor on myeloid cells. (2008)
  • Author(s): Can I et. al.
  • Journal Title: The Journal of Immunology 180 Pages: 207-213
  • Peer Reviewed
• [Journal Article] LFA-1 decreases the antigen dose for T cell activation in vivo. (2008)
  • Author(s): Wang Y et. al.
  • Journal Title: International Immunology 20 Pages: 1119-1127
  • Peer Reviewed
• [Journal Article] Caspase-independent cell death by CD300LF(MAIR-V), an inhibitory immunoglobulin-like receptor on myeloid cells (2008)
  • Author(s): Can I, et. al.
  • Journal Title: Journal of Immunology 180:1 Pages: 207-13
  • Peer Reviewed
• [Journal Article] Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcRγ chain on peritoneal macrophages (2007)
  • Author(s): Nakahashi C, Tahara-Hanaoka S, Shibuya A. et.al.(9人中最終著者)
  • Journal Title: J Immun 178 Pages: 765-70
  • Peer Reviewed
• [Journal Article] Th1 and type 1 cytotoxic T cells dominant responses in T-bet overexpression transgenic mice develops allergic contact dermatitis (2007)
  • Author(s): Ishizaki K, Shibuya A, Takahashi S. et.al.(10人中9番目)
  • Journal Title: J Immunol 178 Pages: 605-12
  • Peer Reviewed
• [Journal Article] The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors (2007)
  • Author(s): Hara H, Ishihara C, Shibuya A, Saito T. et.al.(16人中9番目)
  • Journal Title: Nature Immunol 8 Pages: 619-29
  • Peer Reviewed
• [Journal Article] Unusual biochemical features and follicular dendritic cell expression of human Fcα/μ receptor (2007)
  • Author(s): Kikuno K, Shibuya A, Kubagawa H. et.al.(10人中9番目)
  • Journal Title: Eur J Immunol 37 Pages: 3540-3550
  • URL: http://www.tulips.tsukuba.ac.jp/dspace/handle/2241/97904/browse-title
  • Peer Reviewed
• [Journal Article] Unusual biochemical features and follicular dendritic cell expression of human Fcalpha/mu receptor. (2007)
  • Author(s): Kikuno K, et. al.
  • Journal Title: Eur J Immunol 37 Pages: 3540-3550
  • Peer Reviewed
• [Journal Article] The adaptor protein CARD9 is essential for the activation of myeloid cells through ITAM-associated and Toll-like receptors (2007)
  • Author(s): Hara H, et. al.
  • Journal Title: Nature Immunology 180:1 Pages: 207-13
  • Peer Reviewed
• [Journal Article] Activation of neutrophils by a novel triggering immunoglobulin-like Receptor MAIR-IV. (2007)
  • Author(s): Nakano T, et. al.
  • Journal Title: Molecular immunology 45(1) Pages: 289-94
  • Peer Reviewed
• [Journal Article] Dual assemblies of an activating immune receptor, MAIR-II, with ITAM-bearing adapters DAP12 and FcR chain on peritoneal macrophages. (2007)
  • Author(s): Nakahashi C, et. al.
  • Journal Title: Journal of Immunology 15;178(2) Pages: 765-70
  • Peer Reviewed
• [Journal Article] A critical role of LFA-1 in the development of Th17 cells and induction of experimental autoimmune encephalomyelitis. (2007)
  • Author(s): Wang Y, et. al.
  • Journal Title: Biochem Biophys Res Commun 23;353 Pages: 857-62
  • Peer Reviewed
• [Journal Article] Th1 and Type 1 Cytotoxic T Cells Dominate the Responses in Tbet Over-expression Transgenic Mice that Develop Contact Dermatitis. (2007)
  • Author(s): Ishizaki K, et. al.
  • Journal Title: Journal of Immunology 178(1) Pages: 605-12
  • Peer Reviewed
• [Journal Article] Expression of a Splicing Isoform of MAIR-V(CD300LF), an inhibitory immunoglobulin-like receptor on myeloid cells.
  • Author(s): Can I, et. al.
  • Journal Title: Hybridoma In preess
  • Peer Reviewed
• [Presentation] Enhanced humoral Immune responses against T-independent antigens in Fca/mR-deficient mice (2008)
  • Author(s): Shibuya A.
  • Organizer: International Symposium of 38^<th> meeting of the Japanese Society for Immunology
  • Place of Presentation: Kyoto
  • Year and Date: 2008-12-01
• [Presentation] Immune responses by the family of activating and inhibitory myeloid associated-immunoglobulin-like receptors (MAIR) (2008)
  • Author(s): Shibuya A.
  • Organizer: 57^<th> fall Conference of Korean Association of Immunologists
  • Place of Presentation: Seoul
  • Year and Date: 2008-11-13
• [Presentation] Immune responses by the family of activating and inhibitory myeloid associated-immunoglobulin-like receptors (MAIR). (2008)
  • Author(s): Shibuya A
  • Organizer: 57th /fall Conference of Korean Association of Immunologists.
  • Place of Presentation: Seoul, Korea
  • Year and Date: 2008-11-13
• [Presentation] Accelerated tumor growth in mice deficient in DNAM-1 receptor. (2008)
  • Author(s): Shibuya A
  • Organizer: 11th meeting of the Society for Natural Immunity
  • Place of Presentation: Fremantle, Australia
  • Year and Date: 2008-10-28
• [Presentation] Accelerated tumor growth in mice deficient in DNAM-1 receptor (2008)
  • Author(s): Shibuya A.
  • Organizer: 1^<th> meeting of the Society for Natural Immunity. Perth
  • Place of Presentation: Australia
  • Year and Date: 2008-10-27
• [Presentation] Enhanced humoral Immune responses against T-independent antigens in Fca/mR-deficient mice. (2008)
  • Author(s): Shibuya A.
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: New Heaven, USA.
  • Year and Date: 2008-08-07
• [Presentation] Enhanced humoral Immune responses against T-independent an tigens in Fcα/μR-deficient mice. (2008)
  • Author(s): Shibuya A
  • Organizer: FASEB Summer Research Conference
  • Place of Presentation: New Haven, USA
  • Year and Date: 2008-08-07
• [Presentation] Negative regulation of IgA production by the Fcα/μ recepto, an Fc receptor for IgA and IgM. (2008)
  • Author(s): KURITA Naoki, HONDA Shin-ichiro, CHO Yukiko, USUI Kenta, TAKESHITA Kie, TAHARA-HANAOKA Satoko, SHIBUYA Kazuko and SHIBUYA Akira.
  • Organizer: 第3回JSI-RCAI免疫ワークショップ
  • Place of Presentation: 理化学研究所・横浜研究所
  • Year and Date: 2008-03-14
• [Presentation] Activation of neutrophils by a novel triggering immunoglobulin-like receptor MAIR-IV (2008)
  • Author(s): Takako Nakano, Satoko Tahara-Hanaoka, Chigusa Nakahashi-Oda, Ismail Can, Naoya Totsuka, Kaori Hitomi, Satoru Someya, Shin-ichiro Honda, Kazuko Shibuya, and Akira Shibuya.
  • Organizer: Keystone Symposia
  • Place of Presentation: Keystone USA
  • Year and Date: 2008-02-25
• [Presentation] Enhanced humoral Immune responses against T-independent an tigens in Fcα/μR-deficient mice. (2008)
  • Author(s): Shibuya A
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Increased anti-PC natural IgM production and resistance against Streptococcus pneuoniae infection in mice deficient in Fcα/μR. an Fc receptor for IgA and IgM (2008)
  • Author(s): HONDA Shin-ichiro
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Identification and characterization of a novel inhibitory immunoglobulin-like receptor, MBIR (2008)
  • Author(s): Satoko Tahara-Hanaoka
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Prolonged survival of MAIR-I (CD300a)-deficient mice from acute septic peritonitis (2008)
  • Author(s): Chigusa Nakahashi-Oda
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Involvement of DNAM-1 (CD226) in development of graft-versus-host disease (2008)
  • Author(s): Tsukasa Nabekura
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] Negative regulation of IgA production by the Fcα/μR, an Fc receptor for IgA and IRM (2008)
  • Author(s): Naoki Kurita
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] MAIR- II(CD300d) amplifies TLRs-mediated inflammation and is crucial mediator of murine sepsis model. (2008)
  • Author(s): Naoya Totsuka
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] A novel role of CD155 as a co-stimulatory molecule on CD4 + helper T cells in mice (2008)
  • Author(s): Yumi Yamashita
  • Organizer: 第38回日本免疫学会総会・学術集会
  • Place of Presentation: 京都
• [Presentation] 精子細胞分化におけるFcα/μRの役割 (2007)
  • Author(s): 臼井健太, 本多伸一郎, 渋谷 彰
  • Organizer: 特定領域研究「生殖細胞の発生プロセス・再プログラム化とエピジェネティクス」公開シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2007-11-02
• [Presentation] ITIMを持つ免疫受容体MAIR-Vの機能解析 (2007)
  • Author(s): Ismail Can, Satoko Tahara-Hanaoka, Shin-ichiro Honda, Kazuko Shibuya, Akira Shibuya.
  • Organizer: 第69回 日本血液学会
  • Place of Presentation: 神奈川
  • Year and Date: 2007-10-12
• [Presentation] 好中球の活性化を制御する新規ペア型受容体MAIR-IV (2007)
  • Author(s): 中埜 貴子、田原 聡子、中橋 ちぐさ、Ismail Can、戸塚 直也、本多 伸一郎、渋谷 和子、渋谷 彰
  • Organizer: 第69回 日本血液学会
  • Place of Presentation: 神奈川
  • Year and Date: 2007-10-12
• [Presentation] Control of germinal center reaction against T-independent antigens by the Fc(alpha)/(mu)receptor. (2007)
  • Author(s): Akira Shibuya.
  • Organizer: 13th International Congress of Immunology
  • Place of Presentation: Rio de Janeiro-Brazil
  • Year and Date: 2007-08-21
• [Presentation] ヘルパーT細胞免疫応答におけるDNAM-1の役割 (2007)
  • Author(s): 甲斐平康、渋谷和子、井口研子、田原聡子、本多伸一郎、渋谷彰
  • Organizer: KTCC
  • Place of Presentation: 京都
  • Year and Date: 2007-06-16
• [Presentation] Control of Germinal Center Reaction against TIndependent Antigens by the Fc(alpha)/(mu)Receptor. (2007)
  • Author(s): Akira Shibuya, Ukiko Cho, Satoko Tahara-Hanaoka, kazuko Shibuiya, Shin-ichiro Honda.
  • Organizer: 94th Annual Meeting The American Association of Immunologists.
  • Place of Presentation: USA
  • Year and Date: 2007-05-21
• [Presentation] Physical and functional association of MAIR-II with ITAM containing adapters FcRγ chain as well as DAP12 in activated macrophages. (2007)
  • Author(s): A Shibuya, C Nakahashi, N Totsuka, S Tahara-Hanaoka.
  • Organizer: Keystone Symposia
  • Place of Presentation: Colorado, USA
  • Year and Date: 2007-04-14
• [Presentation] IgM suppresses humoral immune responses against T-independent antigens via the Fcα/μR (2007)
  • Author(s): HONDA Shin-ichiro, CHO Yukiko, USUI Kenta, KURITA Naoki, TAKESHITA Kie^1, TAKAHASHI Satoru, KINOSHITA Taroh, FUJITA Teizo、 TAHARA-HANAOKA Satoko, SHIBUYA Kazuko, SHIBUYA Akira.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Caspase-independent cell death by MAIR-V(CD300LF), immunoglobulin-like receptor on myeloid cells (2007)
  • Author(s): Ismail Can, Satoko Tahara-Hanaoka, Chigusa Nakahashi, Takako Nakano, Kaori Hitomi, Shin-ichiro Honda, Kazuko Shibuya, Akira Shibuya
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] A critical role of DNAM-1 in tumor immunosurveillance (2007)
  • Author(s): Iguchi Akiko, SHIBUYA Kazuko, KAI Hirayasu, TAHARA-HANAOKA Satoko, HONDA Shinichiro, SHIBUYA A Akira.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Analysis for the variants of Fcα/μR, a novel Fcreceptor for IgA and IgM, expressed in the kidney and testis. (2007)
  • Author(s): USUI Kenta, HONDA Shin-ichiro, KURITA Naoki, MIYAMOTO Akitomo, CHO Yukiko, TAHARA-HANAOKA Satoko, SHIBUYA Kazuko, SHIBUYA Akira
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Negative regulation of IgA production by the Fca/mR, an Fc receptor for IgA and IgM. (2007)
  • Author(s): KURITA Naoki, HONDA Shin-ichiro, CHO Yukiko, USUI Kenta, TAKESHITA Kie, TAHARA Satoko, SHIBUYA Kazuko, SHIBUYA Akira.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] A critical role of LFA-1 in the development of Th17 cells and induction of experimental autoimmune encep halomyelitis. (2007)
  • Author(s): SHIBATA Kai^1, WANG Yinan^1, KAI Hirayasu^1, TAHARA-HANAOKA Satoko^1, HONDA Shin-ichiro^1, SHIBUYA Akira^1, SHIBUYA Kazuko.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Critical role of DNAM-1(CD226)in the development of Th1 cells. (2007)
  • Author(s): KAI Hirayasy, IGUCHI Akiko, WANG Yinan, YAMASHITA Yumi, YASUI Teruhito, KIKUTANI Hitoshi, THARA-HANAOKA Satoko, HONDA Shin-ichiro, SHIBUYA Akira, SHIBUYA Kazuko.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] A novel triggering neutrophil receptor, MAIR-IV, transduces activating signal via FcRγ-independent as well as dependent pathways. (2007)
  • Author(s): Takako Nakano, Satoko Tahara-Hanaoka, Chigusa Nakahashi, Can Ismail, Naoya Totsuka, Kaori Hitomi, Satoru Someya, Shin-ichiro Honda, Kazuko Shibuya, Akira Shibuya.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] ITIM-bearing Immunoglobulin-like receptor, MAIR-I(CD300a)modulates the inflammatory responses in murine sepsis. (2007)
  • Author(s): Chigusa Nakahashi-Oda, Satoko Tahara-Hanaoka, Kaori Hitomi, Takako Nakano, Can Ismail, Naoya Totsuka, Teruhito Yasui, Hitoshi Kikutani, Shin-ichiro Hond Kazuko Shibuya, Akira Shibuya.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Presentation] Molecular characterization of Fcα/μR, a novel Fc receptor for IgA and IgM. (2007)
  • Author(s): CHO Yukiko, HONDA Shin-ichiro, USUI Kenta, KURITA Naoki, TAKESHITA Kie, TAHARA-HANAOKA Satoko, SHIBUYA Kazuko and SHIBUYA Akira.
  • Organizer: 第37回 日本免疫学会総会・学術集会
  • Place of Presentation: 東京
• [Remarks]
  • URL: http://www.tulips.tsukuba.ac.jp/dspace/handle/2241/97904/browse-title
• [Patent(Industrial Property Rights)] Fcα/μレセプターを介する生体機能調節物質のスクリーニング方法 (2008)
  • Inventor(s): 渋谷彰、本多伸一郎
  • Industrial Property Rights Holder: 渋谷彰、本田伸一郎
  • Filing Date: 2008-10-10
• [Patent(Industrial Property Rights)] 移植片対宿主病予知マーカーおよびその利用 (2008)
  • Inventor(s): 渋谷彰
  • Industrial Property Rights Holder: 渋谷彰
  • Filing Date: 2008-12-23
  • Overseas
• [Patent(Industrial Property Rights)] cα/μレセプターを介する生体機能調節物質のスクリーニシグ方法 (2008)
  • Inventor(s): 渋谷彰,本多伸一郎
  • Industrial Property Rights Holder: 渋谷彰,本多伸一郎
  • Industrial Property Number: 2008-263584
  • Filing Date: 2008-10-10