■ 氏名
清水 健之 (シミズ タケユキ)
SHIMIZU Takeyuki

■ 所属部局/職名
Research and Education Faculty, Medical Sciences Cluster, Basic Medicine Unit/Associate Professor
教育研究部 医療学系 基礎医学部門/准教授

■ 学部・学科・コース等
Medical School, Medical Course, Department of Immunology
医学部 医学科 免疫学

■ 連絡先
住 所高知県南国市岡豊町小蓮 高知大学医学部免疫学教室
電 話088-880-2318 (内線22601)
F A X088-880-2320
E-Mailtshimizu●kochi-u.ac.jp    (送信の際は“●”を半角の“@”に変更して送信してください。)
U R L

■ 出身大学院・研究科等
京都大学 博士(理学研究科 ) 1995 (修了)

■ 出身学校・専攻等
京都大学 (理学部 ) 1990 (卒業)

■ 取得学位
博士(理学) (課程) 京都大学 分子生物学

■ 研究職歴
1995 バーゼル免疫学研究所(スイス) サマースチューデント
1995-2001 バーゼル免疫学研究所(スイス) 研究員
2001-2004 東京理科大学生命科学研究所 助手
2004-2010 札幌医科大学医学部 講師
2010 高知大学医学部 助教
2010- 高知大学医学部 准教授

■ 委員歴・役員歴

■ 受賞学術賞

■ 所属学会
日本分子生物学会
 ( )
日本免疫学会
 ( )
日本生化学会
 ( )

■ 専門分野
免疫学、分子生物学、生化学

■ 主な研究テーマ・活動
免疫反応の活性化、調節、成熟機構の解析(B細胞の活性化、親和性向上、免疫記憶の形成)

■ 研究についてのPR
脊椎動物にみられる高度に進化した獲得免疫システムは、病原体やウィルス感染細胞を排除することで我々の体を守っている。この免疫システムの活性化メカニズムを理解し、適切な免疫反応を効率よく誘導する手法の開発を目指す。特に以下の点に注目して研究している。

B細胞免疫応答の経時的変化
外来異物の侵入によって、抗原特異的B細胞が活性化され、異物に対する抗体が産生される。初期に産生される抗体は抗原親和性の低いIgMタイプのものが多いが、時間経過に伴ってIgGなど他のタイプの抗体が増えてくる。さらに抗体遺伝子に高頻度に突然変異が起こり、抗原に対する親和性が上昇する。このような産生される抗体の特徴の経時的変化は、生体内でのB細胞の「進化」の結果と考えられている。つまり、生体にとってより良い抗体を産生するB細胞が選択されて生き残っているのである。「どのような抗体が生体にとってよい抗体なのか?」、「生体内ではどのような分子メカニズムで良い抗体が作られ選択されるのか?」について研究することで、「良い抗体を作らせる方法の開発」につなげられると考えている。

コレクチンによる免疫反応の調節
コレクチンは自然免疫生体防御に関わるレクチン分子で、様々な病原体に結合してそれらの排除に働いている。さらに近年、免疫細胞に発現するレセプター分子に結合して免疫反応調節機能があることが示されている。現在、コレクチンと抗体機能の関連について、解析している。

T細胞の標的認識
T細胞は、標的細胞の表面にあるMHC+ペプチドを認識している。T細胞による標的細胞の認識機構や、ヘルパーT細胞と細胞障害性T細胞の協調を、特に抗腫瘍反応について研究している。

■ 社会人・生徒を対象として可能な講演・授業(例えば講演題目)

■ 研究業績(論文・解説)
Deciphering antigen-responding antibody repertoires by using next-generation sequencing and confirming them through antibody-gene synthesis
 Biochem. Biophys. Res. Commun. (Naoko Kono, Lin Sun, Hiroyuki Toh, Takeyuki Shimizu, Xue Hambing, Osamu Numata, Manabu Ato, Kazuo Ohnishi, Shigeyuki Itamura) 487/2, 300-306 2017 (学術雑誌) 10.1016/j.bbrc.2017.04.054

Somatic hypermutation of immunoglobulin genes in Rad18 knockout mice
 DNA Repair (Takeyuki Shimizu, Satoshi Tateishi, Yuki Tanoue, Takachika Azuma, Haruo Ohmori) 50/, 54-60 2017 (学術雑誌) 10.1016/j.dnarep.2016.12.008

High affinity IgM+ memory B cells are generated through a germinal center-dependent pathway
 Mol. Immunol. (Yasushi Hara, Yasuyuki Tashiro, Akikazu Murakami, Miyuki Nishimura, Takeyuki Shimizu, Masato Kubo, Peter D. Burrows and Takachika Azuma) 68/2, 617-627 2015 (学術雑誌) 10.1016/j.molimm.2015.10.003

An asymmetric antibody repertoire is shaped between plasmablast and plasma cells after secondary immunization with (4-hydroxy-3-nitrophenyl)acetyl chicken γ-globulin
 Int. Immunol. (Yasuyuki Tashiro, Akikazu Murakami, Ryo Goizuka, Takeyuki Shimizu, Hidehiro Kishimoto, and Takachika Azuma) 27/12, 609-620 2015 (学術雑誌) 10.1093/intimm/dxv040, PMID: 26152273

Detection and isolation of anti-hapten antibody-secreting cells by cellular affinity matrix technology
 J. Immunol. Methods (Takeyuki Shimizu, Takachika Azuma) 422/, 80-86 2015 (学術雑誌) 10.1016/j.jim/2015.04.006

BILL-cadherin/cadherin-17 contributes to the survival of memory B cells
 PLoS One (Shuichi Funakoshi, Takeyuki Shimizu, Osamu Numata, Fritz Melchers, Kazuo Ohnishi) 10/1, e0117566 2015 (学術雑誌)

Low-affinity IgM antibodies lacking somatic hypermutations are produced in the secondary response of C57BL/6 mice to (4-hydroxy-3-nitrophenyl)acetyl happen
 Int. Immunol. (Akikazu Murakami, Hayato Moriyama, Mina Osako-Kabasawa, Kanako Endo, Miyuki Nishimura, Keiko Udaka, Masamichi Muramatsu, Tasuku Honjo, Takachika Azuma, Takeyuki Shimizu) 26/4, 195 2014 (学術雑誌)

In vivo role of aldehyde reductase
 Biochimica et Biophysica Acta (Motoko Takahashi, Satoshi Miyata, Junichi Fujii, Yoko Inai, Shigemitsu Ueyama, Motoko Araki, Tomoyoshi Soga, Reiko Fujinawa, Chiaki Nishitani, Shigeru Ariki, Takeyuki Shimizu, Tomomi Abe, Yoshito Ihara, Morimitsu Nishikimi, Yasunori Kozutsumi, Naoyuki Taniguchi, and Yoshio Kuroki) 1820/11, 1787-1796 2012 (学術雑誌)

Pulmonary Collectins Play Distinct Roles in Host Defense against Mycobacterium avium
 J. Immunol. (Shigeru Ariki, Takashi Kojima, Shinsei Gasa, Atsushi Saito, Chiaki Nishitani, Motoko Takahashi, Takeyuki Shimizu, Yuichiro Kurimura, Norimasa Sawada, Nobuhiro Fujii, and Yoshio Kuroki) 187/, 2586-2594 2011 (学術雑誌)

The amino acid residue at position 95 and the third CDR region in the H chain determine the ceiling affinity and the maturation pathway of an anti-(4-hydroxy-3-nitrophenyl)acetyl antibody.
 Mol. Immunol. (Akikazu Murakami, Yuka Takahashi, Miyuki Nishimura, Takeyuki Shimizu, and Takachika Azuma) 48/, 48-58 2010 (学術雑誌)

Pulmonary Collectins Protect Macrophages against Pore-forming Activity of Legionella pneumophila and Suppress Its Intracellular Growth
 J. Biol. Chem. (Kaku Sawada, Shigeru Ariki, Takashi Kojima, Atsushi Saito, Masami Yamazoe, Chiaki Nishitani, Takeyuki Shimizu, Motoko Takahashi, Hiroaki Mitsuzawa, Shin-ichi Yokota, Norimasa Sawada, Nobuhiro Fujii, Hiroki Takahashi, and Yoshio Kuroki) 285/, 8434-8443 2010 (学術雑誌)

Mannose binding lectin and lung collectins interact with Toll-like receptor 4 and MD-2 by different mechanisms
 Biochim. Biophys. Acta. (Takeyuki Shimizu, Chiaki Nishitani, Hiroaki Mitsuzawa, Shigeru Ariki, Motoko Takahashi, Katsuki Ohtani, Nobutaka Wakamiya, and Yoshio Kuroki) 1790/, 1705-1710 2009 (学術雑誌)

Mutational analysis of Cys88 of Toll-like receptor 4 highlights the critical role of MD-2 in cell surface receptor expression
 Int. Immunol. (Chiaki Nishitani, Motoko Takahashi, Hiroaki Mitsuzawa, Takeyuki Shimizu, Shigeru Ariki, Norio Matsushima, and Yoshio Kuroki) 21/, 825-834 2009 (学術雑誌)

Pulmonary surfactant protein D inhibits lipopolysaccharide (LPS)-induced inflammatory cell responses by altering LPS binding to its receptors
 J. Biol. Chem. (Masami Yamazoe, Chiaki Nishitani, Motoko Takahashi, Tsuyoshi Katoh, Shigeru Ariki, Takeyuki Shimizu, Hiroaki Mitsuzawa, Kaku Sawada, Dennis R. Voelker, Hiroki Takahashi, and Yoshio Kuroki) 283/, 35878-35888 2008 (学術雑誌)

Pulmonary surfactant protein D binds MD-2 through the carbohydrate recognition domain
 Biochemistry (Xiaomeng Nie, Chiaki Nishitani, Masami Yamazoe, Shigeru Ariki, Motoko Takahashi, Takeyuki Shimizu, Hiroaki Mitsuzawa, Kaku Sawada, Kelly Smith, Erika Crouch, Hisato Nagae, Hiroki Takahashi, and Yoshio Kuroki) 47/, 12878-12885 2008 (学術雑誌)

T cells specific to hapten-carrier but not to carrier alone assist in the production of anti-hapten and anti-carrier antibodies
 Int. Immunol. (Takeyuki Shimizu, Yuko Osaka, Chihiro Banri-Koike, Maiko Yoshida, Kanako Endo, Koji Furukawa, Masayuki Oda, Akikazu Murakami, Shuhei Ogawa, Ryo Abe, and Takachika Azuma) 19/, 1157-1164 2007 (学術雑誌)

The microtubule-binding protein Hook3 interacts with a cytoplasmic domain of scavenger receptor A
 J. Biol. Chem. (Hitomi Sano, Masaho Ishino, Helmut Kramer, Takeyuki Shimizu, Hiroaki Mitsuzawa, Chiaki Nishitani, and Yoshio Kuroki) 282/, 7973 2007 (学術雑誌)

Strategy for affinity maturation of an antibody with high evolvability to (4-hydroxy-3-nitrophenyl)acetyl hapten
 Mol. Immunol. (Koji Furukawa, Takeyuki Shimizu, Akikazu Murakami, Ryo Kono, Masatoshi Nakagawa, Takuma Sagawa, Ichiro Yamato, and Takachika Azuma) 44/, 2436-2445 2007 (学術雑誌)

Toll-like receptor 4 region Glu24-Lys47 is a site for MD-2 binding: Importance of Cys29 and Cys40
 J. Biol. Chem. (Chiaki Nishitani, Hiroaki Mitsuzawa, Hitomi Sano, Takeyuki Shimizu, Norio Matsushima, Yoshio Kuroki) 281/, 38322-38329 2006 (学術雑誌)

The 6-fluoro-8-methoxy quinolone, gatifloxacin, down-regulates interleukin-8 production in prostate cell line PC-3
 Antimicrob. Agents Chemother. (Koh Takeyama, Hiroaki Mitsuzawa, Chiaki Nishitani, Takeyuki Shimizu, Hitomi Sano, Yasuharu Kunishima, Satoshi Takahashi, Hiroshi Hotta, Masanori Matsukawa, Ken-ichiro Shibata, Taiji Tsukamoto, and Yoshio Kuroki) 51/, 162-168 2007 (学術雑誌)

Surfactant protein A without the interruption of Gly-X-Y repeats loses a kink of oligomeric structure and exhibits impaired phospholipid liposome aggregation ability
 Biochemistry (Tatsuki Uemura, Hitomi Sano, Tsuyoshi Katoh, Chiaki Nishitani, Hiroaki Mitsuzawa, Takeyuki Shimizu, and Yoshio Kuroki) 45/, 14543-14551 2006 (学術雑誌)

Recombinant soluble forms of extracellular TLR4 domain and MD-2 inhibit lipopolysaccharide binding on cell surface and dampen lipopolysaccharide-induced pulmonary inflammation in mice
 J. Immunol. (Hiroaki Mitsuzawa, Chiaki Nishitani, Naoki Hyakushima, Takeyuki Shimizu, Hitomi Sano, Norio Matsushima, Koichi Fukase, and Yoshio Kuroki) 177/, 8133-8139 2006 (学術雑誌)

Mannose-binding lectin augments the uptake of lipid A, Staphylococcus aureus, and Escherichia coli by Kupffer cells through increased cell surface expression of scavenger receptor A
 J. Immunol. (Kei Ono, Chiaki Nishitani, Hiroaki Mitsuzawa, Takeyuki Shimizu, Hitomi Sano, Hiroshi Suzuki, Tatsuhiko Kodama, Nobuhiro Fujii, Koichi Fukase, Koichi Hirata, and Yoshio Kuroki) 177/, 5517-5523 2006 (学術雑誌)

Human pulmonary surfactant protein D binds the extracellular domains of Toll-like receptors 2 and 4 through the carbohydrate recognition domain by a mechanism different from its binding to phosphatidylinositol and lipopolysaccharide
 Biochemistry (Madoka Ohya, Chiaki Nishitani, Hitomi Sano, Chieko Yamada, Hiroaki Mitsuzawa, Takeyuki Shimizu, Tsuyoshi Sato, Kelly Smith, Erika Crouch, and Yoshio Kuroki) 45/, 8657-8664 2006 (学術雑誌)

Surfactant protein A directly interacts with TLR4 and MD-2 and regulates inflammatory cellular response: importance of supratrimeric oligomerization
 J. Biol. Chem. (Chieko Yamada, Hitomi Sano, Takeyuki Shimizu, Hiroaki Mitsuzawa, Chiaki Nishitani, Tetsuo Himi, and Yoshio Kuroki) 281/, 21771-21780 2006 (学術雑誌)

Alloiococcus otitidis is a ligand for collectins and Toll-like receptor 2, and its phagocytosis is enhanced by collectins
 Eur. J. Immunol. (Masanori Konishi, Chiaki Nishitani, Hiroaki Mitszawa, Takeyuki Shimizu, Hitomi Sano, Atsushi Harimaya, Nobuhiro Fujii, Tetsuo Himi, and Yoshio Kuroki) 36/, 1527-2536 2006 (学術雑誌)

The prostate cell lines secrete IL-8 in response to Mycoplasma hominis through Toll-like receptor 2-mediated mechanism
 The Prostate (Koh Takeyama, Hiroaki Mitsuzawa, Takeyuki Shimizu, Masanori Konishi, Chiaki Nishitani, Hitomi Sano, Yasuharu Kunishima, Masanori Matsukawa, Satoshi Takahashi, Ken-ichiro Shibata, Taiji Tsukamoto, and Yoshio Kuroki) 66/, 386-391 2006 (学術雑誌)

Generation of monoclonal antibodies against chromosomal antigens that have a high sequence similarity between human and mouse
 J. Biothechnol. (Tsunehito Higashi, Shuichi Miyakawa, Susumu Uchiyama, Sachihiro Matsunaga, Hideaki Takata, Satoru Fujimoto, Masanori Noda, Akiko Terauchi, Takeyuki Shimizu, Masayuki Oda, Takachika Azuma, Kiichi Fukui) 120/, 262-272 2005 (学術雑誌)

Normal Immunoglobulin gene somatic hypermutation in Polkappa-Poliota double-deficient mice
 Immunol. Lett. (Takeyuki Shimizu, Takachika Azuma, Mariko Ishiguro, Naoko Kanjo, Shuichi Yamada, Haruo Ohmori) 98/, 259-264 2005 (学術雑誌)

Lymphocyte-expressed BILL-cadherin/cadherin-17 contributes to the development of B cells at two stages
 Eur. J. Immunol. (Kazuo Ohnishi, Fritz Melchers, and Takeyuki Shimizu) 35/, 957-963 2005 (学術雑誌)

Affinity maturation of secreted IgM pentamers on B cells
 Int. Immunol. (Takeyuki Shimizu, Yuko Kozono, Haruo Kozono, Masayuki Oda, and Takachika Azuma) 16/, 675-685 2004 (学術雑誌)

The absence of DNA polymerase kappa does not affect somatic hypermutation of the mouse immunoglobulin heavy chain gene
 Immunol. Lett. (Takeyuki Shimizu, Yoichi Shinkai, Tomoo Ogi, Haruo Ohmori, and Takachika Azuma) 86/, 265-270 2003 (学術雑誌)

Estimation of the relative affinity of B cell receptor by flow cytometry
 J. Immunol. Meth. (Takeyuki Shimizu, Masayuki Oda, and Takachika Azuma) 278/, 33-44 2003 (学術雑誌)

VpreB1/VpreB2/lambda5 triple deficient mice show impaired B cell development but functional allelic exclusion of the IgH locus
 J. Immunol. (Takeyuki Shimizu, Cornelia Mundt, Steve Licence, Fritz Melchers, and Inga-Lill Martensson) 168/, 6286-6293 2002 (学術雑誌)

Loss of precursor B cell expansion but not allelic exclusion in VpreB1/VpreB2 double-deficient mice
 J. Exp. Med. (Cornelia Mundt, Steve Licence, Takeyuki Shimizu, Fritz Melchers, and Inga-Lill Martensson) 193/, 435-445 2001 (学術雑誌)

The identification of a non-classical cadherin expressed during B cell development and its interaction with surrogate light chain
 J. Biol. Chem. (Kazuo Ohnishi, Takeyuki Shimizu, Hajime Karasuyama, and Fritz Melchers) 275/, 31134-31144 2000 (学術雑誌)

■ 研究業績(著書)

■ 研究業績(口頭・ポスター)

■ 研究業績(特許)

■ 研究業績(その他の活動)


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