平成20年 免疫病態研究部門(旧情報細胞学部門)

1998年秋に当部門に松本が着任して以来、この10年間、自己免疫疾患の病態解明を中心課題とする免疫学研究に取り組んできた。


1)自己免疫疾患の病態解明

当センターに着任後、リンパ組織形成に障害をもつ突然変異マウス(aly)の二次リンパ組織形成障害のメカニズム解明に着手し、alyマウスがリンホトキシン受容体のシグナル伝達に障害をもつことを見出した。同時期に他のグループによってalyマウスの原因遺伝子がNF-?B-inducing kinase(NIK)であることが報告されたが、私どもはalyマウスの自己免疫病態に着目し、NIKが胸腺の細胞構築化を介して自己寛容の成立機構に働くことを明らかにした。また、遺伝性自己免疫疾患の原因遺伝子 AIREの胸腺での働きに注目してAIRE欠損マウスやAIRE/GFPノックインマウスを作製して、現在、AIREによる自己寛容成立機構の分子メカニズム解明に主力を注いでいる。他方、自己免疫疾患の定義そのものを見直す必要があると考え、非定型的な自己免疫疾患と言える乾癬(psoriasis)の病態解析にも着手し、最近、その第一報を発表した。このようにようやく研究対象も定まり徐々にではあるが論文を発表しつつある。しかしながら、インパクトの大きな成果をあげるには至っていない。事実、これまでのところ当部門からの業績と言える原著論文は12報と十分ではない(他、invited review2報)。これまでの低い生産性を一掃すべく、質・量ともに納得のいく論文を発表する必要がある。さらに、独創的な着眼点をもって研究に取り組まなければ免疫学における難題である自己免疫疾患の病態解明に寄与することは出来ないと考えており、新たな方法論の導入も必要である。


2)発生工学技術を用いた免疫学研究

当センターに着任後、自らの免疫学研究に寄与し、かつ当センターにおける動物実験を活性化できるよう発生工学技術の確立に取り組んできた。しかしながら、自力で樹立にこぎつけることが出来た遺伝子改変マウスはこれまでのところ数系統のみであり、十分とは言えない。酵素センターの諸部門や蔵本キャンパス内の研究室で使用されるマウスの凍結保存卵の作製や融解といったサービス業務には一定の貢献ができたものの、研究推進力としては未だ十分とは言えず、今後も技術者の育成を中心にインフラ整備の改善に粘り強く取り組んでゆく必要がある。

 

業績
  1. Segawa, H., Onitsuka, A., Kuwahata, M., Hanabusa, E., Furutani, J., Kaneko, I., Tomoe, Y., Aranami, F., Matsumoto, N., Ito, M., Matsumoto, M., Li, M., Amizuka, N., and Miyamoto, K.-I.
    Type IIc sodium?dependent phosphate transporter regulates calcium metabolism.
    J. Am. Soc. Nephrol. in press. IF: 7.111
  2. Matsumoto, M., Zhou, Y., Matsuo, S., Nakanishi, H., Hirose, K., Oura, H., Arase, S., Ishida-Yamamoto, A., Bando, Y., Izumi, K., Kiyonari, H., Oshima, N., Nakayama, R., Matsushima, A., Hirota, F., Mouri, Y., Kuroda, N., Sano, S., and Chaplin, D.D.
    Targeted deletion of the murine corneodesmosin gene delineates its essential role in skin and hair physiology.
    Proc. Natl. Acad. Sci. USA 105: 6720-6724, 2008. IF: 9.598
  3. Akiyama, T., Shimo, Y., Yanai, H., Qin, J., Ohshima, D., Maruyama, Y., Asaumi, Y., Kitazawa, J., Takayanagi, H., Penninger, J.M., Matsumoto, M., Nitta, T., Takahama, Y., and Inoue, J-I.
    The tumor necrosis factor family receptors RANK and CD40 cooperatively establish the thymic medullary microenvironment and self-tolerance.
    Immunity 29: 423-437, 2008. IF: 19.266
  4. Hikosaka, Y., Nitta, T., Ohigashi, I., Yano, K., Ishimaru, N., Hayashi, Y., Matsumoto, M., Matsuo, K., Penninger, J.M., Takayanagi, H., Yokota, Y., Yamada, H., Yoshikai, Y., Inoue, J-I., Akiyama, T., and Takahama, Y.
    ?The cytokine RANKL produced by positively selected thymocytes fosters medullary thymic epithelial cells that express autoimmune regulator.
    Immunity 29: 438-450, 2008. IF: 19.266
  5. Yano, M., Kuroda, N., Han, H., Horike, M., Nishikawa, Y., Kiyonari, H., Maemura, K., Yanagawa, Y., Obata, K., Takahashi, S., Ikawa, T., Satoh, R., Kawamoto, H., Mouri, Y., and Matsumoto, M.
    Aire controls the differentiation program of thymic epithelial cells in the medulla for the establishment of self-tolerance.
    J. Exp. Med. 205: 2827-2838, 2008. IF: 15.612
  6. Matsumoto, M.
    Transcriptional regulation in thymic epithelial cells for the establishment of self tolerance.
    Arch. Immunol. Ther. Exp. 55: 27-34, 2007. IF: 1.689
  7. Matsumoto, M.
    Autoimmune regulator functions in autoimmunity control.
    Expert Rev. Clin. Immunol. 3: 891-900, 2007. IF: -
  8. Hamazaki, Y., Fujita, H., Kobayashi, T., Choi, Y., Scott, H.S., Matsumoto, M., and Minato, N.
    Medullary thymic epithelial cells expressing Aire represent a unique lineage derived from cells expressing claudin.
    Nature Immunol. 8: 304-311, 2007. IF: 26.218
  9. The Soluble Insulin Receptor Study Group*
    *Obata, T., Yokota, I., Yokoyama, K., Okamoto, E., Kanezaki, Y., Tanaka, Y., Maegawa, H., Teshigawara, K., Hirota, F., Yuasa, T., Kishi, K., Hattori, A., Hashida, S., Masuda, K., Matsumoto, M., Matsumoto, T., Kashiwagi, A., and Ebina, Y.
    Soluble insulin receptor ectodomain is elevated in the plasma of patients with diabetes.
    Diabetes 56: 2028-2035, 2007. IF: 8.261
  10. Ohtani, N., Imamura, Y., Yamakoshi, K., Hirota, F., Nakayama, R., Kubo, Y., Ishimaru, N., Takahashi, A., Hirao, A., Shimizu, T., Mann, D.J., Saya, H., Hayashi, Y., Arase, S., Matsumoto, M., Nakao, K., and Hara, E.
    Visualizing the dynamics of p21Waf1/Cip1 cyclin-dependent kinase inhibitor expression in living animals.
    Proc. Natl. Acad. Sci. USA 104: 15034-15039, 2007. IF: 9.598
  11. Qin, J., Konno, H., Ohshima, D., Yanai, H., Motegi, H., Shimo, Y., Hirota, F., Matsumoto, M., Takaki, S., Inoue, J-I., and Akiyama, T.
    Developmental stage-dependent collaboration between the TNF receptor-associated factor 6 and lymphotoxin pathways for B cell follicle organization in secondary lymphoid organs.
    J. Immunol. 179: 6799-6807, 2007. IF: 6.068
  12. Nakatani, M., Takehara, Y., Sugino, H., Matsumoto, M., Hashimoto, O., Hasegawa, Y., Murakami, T., Uezumi, A., Takeda, S., Noji, S., Sunada, Y., and Tsuchida, K.
    Transgenic expression of a myostatin inhibitor derived from follistatin increases skeletal muscle mass and ameliorates dystrophic pathology in mdx mice.
    FASEB Journal 22: 477-487, 2007. IF: 6.791
  13. Kinoshita, D., Hirota, F., Kaisho, T., Kasai, M., Izumi, K., Bando, Y., Mouri, Y., Matsushima, A., Niki, S., Han, H., Oshikawa, K., Kuroda, N., Maegawa, M., Irahara, M., Takeda, K., Akira, S., and Matsumoto, M.
    Essential role of IkB kinase a in thymic organogenesis required for the establishment of self-tolerance.
    J. Immunol. 176: 3995-4002, 2006. IF: 6.068
  14. Hoshino, K., Sugiyama, T., Matsumoto, M., Tanaka, T., Saito, M., Hemmi, H., Ohara, O., Akira, S., and Kaisho, T.
    IkB kinase a is critical for Toll-like receptor 7- and 9-induced interferon a production.
    Nature 440: 949-953, 2006. IF: 28.751
  15. Niki, S., Oshikawa, K., Mouri, Y., Hirota, F., Matsushima, A., Yano, M., Han, H., Bando, Y., Izumi, K., Matsumoto, M., Nakayama, K.I., Kuroda, N., and Matsumoto, M.
    Alteration of intra-pancreatic target-organ specificity by abrogation of Aire in NOD mice.
    J. Clin. Invest. 116: 1292-1301, 2006. IF: 16.915
  16. Kuroda, N., Mitani, T., Takeda, N., Ishimaru, N., Arakaki, R., Hayashi, Y., Bando, Y., Izumi, K., Takahashi, T., Nomura, T., Sakaguchi, S., Ueno, T., Takahama, Y., Uchida, D., Sun, S., Kajiura, F., Mouri, Y., Han, H., Matsushima, A., Yamada, G., and Matsumoto, M.
    Development of autoimmunity against transcriptionally unrepressed target antigen in the thymus of Aire-deficient mice.
    J. Immunol. 174: 1862-1870, 2005. IF: 6.068
  17. Akiyama, T., Maeda, S., Yamane, S., Ogino, K., Kasai, M., Kajiura, F., Matsumoto, M., and Inoue, J.
    Dependence of self-tolerance on TRAF6-directed development of thymic stroma.
    Science 308: 248-251, 2005. IF: 26.372
  18. Nagai, Y., Kobayashi, T., Motoi, Y., Ishiguro, K., Akashi, S., Saitoh, S., Kusumoto, Y., Kaisho, T., Akira, S., Matsumoto, M., Takatsu, K., and Miyake, K.
    The radioprotective 105/MD-1 complex links TLR2 and TLR4/MD-2 in antibody response to microbial membranes.
    J. Immunol. 174: 7043-7049, 2005. IF: 6.068
  19. Uchida, D., Hatakeyama, S., Matsushima, A., Han, H., Ishido, S., Hotta, H., Kudoh, J., Shimizu, N., Doucas, V., Nakayama, K.I., Kuroda, N., and Matsumoto, M.
    AIRE functions as an E3 ubiquitin ligase.
    J. Exp. Med. 199: 167-172, 2004. IF: 15.612
  20. Kajiura, F., Sun, S., Nomura, T., Izumi, K., Ueno, T., Bando, Y., Kuroda, N., Han, H., Li, Y., Matsushima, A., Takahama, Y., Sakaguchi, S., Mitani, T., and Matsumoto, M.
    NF-kB-inducing kinase establishes self-tolerance in a thymic stroma dependent manner.
    J. Immunol. 172: 2067-2075, 2004. IF: 6.068
  21. Kanezaki, Y., Obata, T., Matsushima, R., Minami, A., Yuasa, T., Kishi, K., Bando, Y., Uehara, H., Izumi, K., Mitani, T., Matsumoto, M., Takeshita, Y., Nakaya, Y., Matsumoto, T., and Ebina, Y.
    K(ATP) channel knockout mice crossbred with transgenic mice expressing a dominant-negative form of human insulin receptor have glucose intolerance but not diabetes.
    Endocrine J. 51: 133-144, 2004. IF: 1.572
  22. Akiyoshi, H., Hatakeyama, S., Pitkanen, J., Mouri, Y., Doucas, V., Kudoh, J., Tsurugaya, K., Uchida, D., Matsushima, A., Oshikawa, K., Nakayama, K.I., Shimizu, N., Peterson, P., and Matsumoto, M.
    Subcellular expression of autoimmune regulator is organized in a spatiotemporal manner.
    J. Biol. Chem. 279: 33984-33991, 2004. IF: 5.581
  23. Sakai, T., Liu, L., Teng, X., Mukai-Sakai, R., Shimada, H., Kaji, R., Mitani, T., Matsumoto, M., Toida, K., Ishimura, K., Shishido, Y., Mak, T.W., and Fukui, K.
    Nucling recruits Apaf-1/pro-caspase-9 complex for the induction of stress-induced apoptosis.
    J. Biol. Chem. 279: 41131-41140, 2004. IF: 5.581
  24. Yuasa, T., Kakuhata, R., Kishi, K., Obata, T., Shinohara, Y., Bando, Y., Izumi, K., Kajiura, F., Matsumoto, M., and Ebina, Y.
    Platelet-derived growth factor stimulates glucose transport in skeletal muscles of transgenic mice specifically expressing PDGF receptor in the muscle, but does not affect blood glucose levels.
    Diabetes 53: 2776-2786, 2004. IF: 8.261
  25. Minami, A., Iseki, M., Kishi, K., Wang, M., Ogura, M., Furukawa, N., Hayashi, S., Yamada, M., Obata, T., Takeshita, Y., Nakaya, Y., Bando, Y., Izumi, K., Moodie, S.A., Kajiura, F., Matsumoto, M., Takatsu, K., Takaki, S., and Ebina, Y.
    Increased insulin sensitivity and hypoinsulinemia in APS knockout mice.
    Diabetes 52: 2657-2665, 2003. IF: 8.261
  26. Matsumoto, M., Yamada, T., Yoshinaga, S.K., Boone, T., Horan, T., Fujita, S., Li, Y., and Mitani, T.
    Essential role of NF-kB-inducing kinase in T cell activation through the TCR/CD3 pathway.
    J. Immunol. 169: 1151-1158, 2002. IF: 6.068
  27. Matsushima, A., Kaisho, T., Rennert, P.D., Nakano, H., Kurosawa, K., Uchida, D., Takeda, K., Akira, S., and Matsumoto, M.
    Essential role of NF-kB-inducing kinase and IkB-kinase a in NF-kB activation through lymphotoxin-b receptor, but not through TNF receptor-I.
    J. Exp. Med. 193: 631-636, 2001. IF: 15.612
  28. Yamada, T., Mitani, T., Yorita, K., Uchida, D., Matsushima, A., Iwamasa, K., Fujita, S., and Matsumoto, M.
    Abnormal immune function of hemopoietic cells from alymphoplasia (aly) mice, a natural strain with mutant NF-kB-inducing kinase.
    J. Immunol. 165: 804-812, 2000. IF: 6.068
  29. Uwai, M., Terui, Y., Mishima, Y., Tomizuka, H., Ikeda, M., Itoh, T., Mori, M., Ueda, M., Inoue, R., Yamada, M., Hayasawa, H., Horiuchi, T., Niho, Y., Matsumoto, M., Ishizaka, Y., Ikeda, K., Ozawa, K., and Hatake, K.
    A new apoptotic pathway for the complement factor B-derived fragment Bb.
    J. Cell. Physiol. 185:280-292, 2000. IF: 3.643
  30. Matsumoto, M., Iwamasa, K., Rennert, P.D., Yamada, T., Suzuki, R., Matsushima, A., Okabe, M., Fujita, S., and Yokoyama, M.
    Involvement of distinct cellular compartments in the abnormal lymphoid organogenesis in lymphotoxin-a-deficient mice and alymphoplasia (aly) mice defined by the chimeric analysis.
    J. Immunol. 163: 1584-1591, 1999. IF: 6.068
  31. Nakano, H., Sakon, S., Koseki, H., Takemori, T., Tada, K., Matsumoto, M., Munechika, E., Sakai, T., Shirasawa, T., Akiba, H., Kobata, T., Santee, M.S., Ware, C.F., Rennert, P.D., Taniguchi, M., Yagita, H., and Okumura, K.
    Targeted disruption of Traf5 gene causes defects in CD40- and CD27 mediated lymphocyte activation.
    Proc. Natl. Acad. Sci. USA 96: 9803-9808, 1999. IF: 9.598