Development of strategy to treat allergic diseases via targeting surface molecules on lymphocytes and intracellular signaling molecules

2010 Fiscal Year Final Research Report

• Project/Area Number: 20390282
• 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 Juntendo University, 大学院・医学研究科, 特任教授 (50009700)
• Co-Investigator(Kenkyū-buntansha): NAKANO Hiroyasu 順天堂大学, 大学院・医学研究科, 准教授 (70276476) ; AKIBA Hisaya 順天堂大学, 大学院・医学研究科, 准教授 (60338316) ; USHIO Hiroko 順天堂大学, 大学院・医学研究科, 准教授 (30317391)
• Project Period (FY): 2008 – 2010
• Keywords: TIMファミリー / マスト細胞 / アレルギー / アポトーシス

Research Abstract

Members of the T-cell immunoglobulin mucin (Tim) family control a variety of immune responses including Th1 and Th2 differentiation of T cells. We found that TIM-3 was expressed on C8+ dendritic cells (DC) and TIM-3 was crucial for clearance of apoptotic cells by phagocytes. Moreover, TIM-3-dependent phagocytosis of apoptotic cells was crucial for cross-presentation of dying cell-associated antigens. On the other hand, TIM-2 was found to be expressed on B cells and induced positive signals into B cells. Therefore, administration of agonistic anti-TIM-2 antibody significantly exacerbated type II collagen-induced arthritis. We next investigated a role for autophagy in the development and function of mast cells. We found that conversion of type I to type II light chain (LC3)-II, a hallmark of autophagy, was constitutively induced in mast cells under full nutrient conditions, and LC3-II localized in secretory granules of mast cells. Although deletion of Atg7 did not impair the development of BMMCs, Atg7(-/-) BMMCs showed severe impairment of degranulation, but not cytokine production upon antigen stimulation.

Research Products

• [Journal Article] Sharpin is a component of the NF-κB activating linear ubiquitin chain assembly complex. (2011)
  • Author(s): Tokunaga F., T.Nakagawa, M.Nakahara, Y.Saeki, M.Taniguchi, S.Sakata, K.Tanaka, H.Nakano, K.Iwai
  • Journal Title: Nature. 471 Pages: 633-636
• [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, H.Nakano.
  • Journal Title: J Allergy Clin Immunol. (in press)
• [Journal Article] Tumor necrosis factor receptor-associated factor (TRAF)2 controls homeostasis of the colon to prevent spontaneous development of murine inflammatory bowel disease. (2011)
  • Author(s): Piao J.H., M.Hasegawa, B.Heissig, K.Hattori, K.Takeda, Y.Iwakura, K.Okumura, N.Inohara, H.Nakano.
  • Journal Title: J Biol Chem (selected as "Papers of the Week" (in press)
• [Journal Article] Notch1-mediated signaling induces MHC class II expression through the activation of class II transactivator promoter III in mast cells. (2011)
  • Author(s): Nakano N., C.Nishiyama, H.Yagita, A.Koyanagi, H.Ogawa, K.Okumura.
  • Journal Title: J Biol Chem. (in press)
• [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, H.Akiba.
  • Journal Title: Arthritis Res Ther 13(in press) Pages: R47
• [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, K.Okumura.
  • Journal Title: Blood 117 Pages: 2211-2222
• [Journal Article] TIM1 is an endogenous ligand for LMIR5/CD300b : LMIR5 deficiency ameliorates mouse kidney ischemia/reperfusion injury. (2010)
  • Author(s): Yamanishi Y., J.Kitaura, K.Izawa, A.Kaitani, Y.Komeno, M.Nakamura, S.Yamazaki, Y.Enomoto, T.Oki, H.Akiba, T.Abe, T.Komori, Y.Morikawa, H.Kiyonari, T.Takai, K.Okumura, T.Kitamura
  • Journal Title: J Exp Med 207 Pages: 1501-1511
• [Journal Article] Staphylococcus aureus membrane and diacylated lipopeptide induce thymic stromal lymphopoietin in keratinocytes through the Toll-like receptor 2-Toll-like receptor 6 pathway. (2010)
  • Author(s): Vu,A.T., T.Baba, X.Chen, T.A.Le, H.Kinoshita, Y.Xie, S.Kamijo, K.Hiramatsu, S.Ikeda, H.Ogawa, K.Okumura, T.Takai
  • Journal Title: J Allergy Clin Immunol 126 Pages: 985-993, 993, e981-983
• [Journal Article] T-cell immunoglobulin mucin-3 determines severity of liver ischemia/reperfusion injury in mice in a TLR4-dependent manner. (2010)
  • Author(s): Uchida Y., B.Ke, M.C.Freitas, H.Yagita, H.Akiba, R.W.Busuttil, N.Najafian, J.W.Kupiec-Weglinski
  • Journal Title: Gastroenterology 139 Pages: 2195-2206
• [Journal Article] The emerging role of T cell immunoglobulin mucin-1 in the mechanism of liver ischemia and reperfusion injury in the mouse. (2010)
  • Author(s): Uchida Y., B.Ke, M.C.Freitas, H.Ji, D.Zhao, E.R.Benjamin, N.Najafian, H.Yagita, H.Akiba, R.W.Busuttil, J.W.Kupiec-Weglinski
  • Journal Title: Hepatology 51 Pages: 1363-1372
• [Journal Article] Combination therapy of established tumors by antibodies targeting immune activating and suppressing molecules. (2010)
  • Author(s): Takeda K., Y.Kojima, T.Uno, Y.Hayakawa, M.W.Teng, H.Yoshizawa, H.Yagita, F.Gejyo, K.Okumura, M.J.Smyth.
  • Journal Title: J Immunol 184 Pages: 5493-5501
• [Journal Article] Premature terminal exhaustion of Friend virus-specific effector CD8+ T cells by rapid induction of multiple inhibitory receptors. (2010)
  • Author(s): Takamura S., S.Tsuji-Kawahara, H.Yagita, H.Akiba, M.Sakamoto, T.Chikaishi, M.Kato, M.Miyazawa
  • Journal Title: J Immunol 184 Pages: 4696-4707
• [Journal Article] Tissue type plasminogen activator regulates myeloid-cell dependent neoangiogenesis during tissue regeneration. (2010)
  • Author(s): Ohki M., Y.Ohki, M.Ishihara, C.Nishida, Y.Tashiro, H.Akiyama, H.Komiyama, L.R.Lund, A.Nitta, K.Yamada, Z.Zhu, H.Ogawa, H.Yagita,K.Okumura, H.Nakauchi, Z.Werb, B.Heissig, K.Hattori
  • Journal Title: Blood 115 Pages: 4302-4312
• [Journal Article] Antimicrobial peptides human beta-defensins and cathelicidin LL-37 induce the secretion of a pruritogenic cytokine IL-31 by human mast cells. (2010)
  • Author(s): Niyonsaba F., H.Ushio, M.Hara, H.Yokoi, M.Tominaga, K.Takamori, N.Kajiwara, H.Saito, I.Nagaoka, H.Ogawa, K.Okumura
  • Journal Title: J Immunol 184 Pages: 3526-3534
• [Journal Article] GATA2 and Sp1 positively regulate the c-kit promoter in mast cells. (2010)
  • Author(s): Maeda K., C.Nishiyama, H.Ogawa, K.Okumura
  • Journal Title: J Immunol 185 Pages: 4252-4260
• [Journal Article] TIM-3 : a novel regulatory molecule of alloimmune activation. (2010)
  • Author(s): Boenisch O., F.D'Addio, T.Watanabe, W.Elyaman, C.N.Magee, M.Y.Yeung, R.F.Padera, S.J.Rodig, T.Murayama, K.Tanaka, X.Yuan, T.Ueno, A.Jurisch, B.Mfarrej, H.Akiba, H.Yagita, N.Najafian
  • Journal Title: J Immunol 185 Pages: 5806-5819
• [Journal Article] Targeting Tim-1 to overcome resistance to transplantation tolerance mediated by CD8 T17 cells. (2009)
  • Author(s): Yuan X., M.J.Ansari, F.D'Addio, J.Paez-Cortez, I.Schmitt, M.Donnarumma, O.Boenisch, X.Zhao, J.Popoola, M.R.Clarkson, H.Yagita, H.Akiba, G.J.Freeman, J.Iacomini, L.A.Turka, L.H.Glimcher, M.H.Sayegh
  • Journal Title: Proc Natl Acad Sci U S A 106 Pages: 10734-10739
• [Journal Article] RANK-RANKL signaling pathway is critically involved in the function of CD4+CD25+ regulatory T cells in chronic colitis. (2009)
  • Author(s): Totsuka T., T.Kanai, Y.Nemoto, T.Tomita, R.Okamoto, K.Tsuchiya, T.Nakamura, N.Sakamoto, H.Akiba, K.Okumura, H.Yagita, M.Watanabe
  • Journal Title: J Immunol 182 Pages: 6079-6087
• [Journal Article] Tim-3 mediates phagocytosis of apoptotic cells and cross-presentation. (2009)
  • Author(s): Nakayama M., H.Akiba, K.Takeda, Y.Kojima, M.Hashiguchi, M.Azuma, H.Yagita, K.Okumura
  • Journal Title: Blood 113 Pages: 3821-3830
• [Journal Article] Notch signaling confers antigen-presenting cell functions on mast cells. (2009)
  • Author(s): Nakano N., C.Nishiyama, H.Yagita, A.Koyanagi, H.Akiba, S.Chiba, H.Ogawa, K.Okumura
  • Journal Title: J Allergy Clin Immunol 123 Pages: 74-81, e71
• [Journal Article] RANKL is necessary and sufficient to initiate development of antigen-sampling M cells in the intestinal epithelium. (2009)
  • Author(s): Knoop K.A., N.Kumar, B.R.Butler, S.K.Sakthivel, R.T.Taylor, T.Nochi, H.Akiba, H.Yagita, H.Kiyono, I.R.Williams
  • Journal Title: J Immunol 183 Pages: 5738-5747
• [Journal Article] Cytokine milieu modulates release of thymic stromal lymphopoietin from human keratinocytes stimulated with double-stranded RNA. (2009)
  • Author(s): Kinoshita H., T.Takai, T.A.Le, S.Kamijo, X.L.Wang, H.Ushio, M.Hara, J.Kawasaki, A.T.Vu, T.Ogawa, H.Gunawan, S.Ikeda, K.Okumura, H.Ogawa
  • Journal Title: J Allergy Clin Immunol 123 Pages: 179-186
• [Journal Article] NKG2A inhibits invariant NKT cell activation in hepatic injury. (2009)
  • Author(s): Kawamura T., K.Takeda, H.Kaneda, H.Matsumoto, Y.Hayakawa, D.H.Raulet, Y.Ikarashi, M.Kronenberg, H.Yagita, K.Kinoshita, T.Abo, K.Okumura, M.J.Smyth
  • Journal Title: J Immunol 182 Pages: 250-258
• [Journal Article] The emerging role of T cell Ig mucin 1 in alloimmune responses in an experimental mouse transplant model. (2008)
  • Author(s): Ueno T., A.Habicht, M.R.Clarkson, M.J.Albin, K.Yamaura, O.Boenisch, J.Popoola, Y.Wang, H.Yagita, H.Akiba, M.J.Ansari, J.Yang, L.A.Turka, D.M.Rothstein, R.F.Padera, N.Najafian, M.H.Sayegh
  • Journal Title: J Clin Invest 118 Pages: 742-751
• [Journal Article] Death receptor 5 mediated-apoptosis contributes to cholestatic liver disease. (2008)
  • Author(s): Takeda K., Y.Kojima, K.Ikejima, K.Harada, S.Yamashina, K.Okumura, T.Aoyama, S.Frese, H.Ikeda, N.M.Haynes, E.Cretney, H.Yagita, N.Sueyoshi, N.Sato, Y.Nakanuma, M.J.Smyth, K.Okumura
  • Journal Title: Proc Natl Acad Sci U S A 105 Pages: 10895-10900
• [Journal Article] B7-H3 contributes to the development of pathogenic Th2 cells in a murine model of asthma. (2008)
  • Author(s): Nagashima O., N.Harada, Y.Usui, T.Yamazaki, H.Yagita, K.Okumura, K.Takahashi, H.Akiba
  • Journal Title: J Immunol 181 Pages: 4062-4071
• [Journal Article] Two different transcription factors discriminate the -315C>T polymorphism of the Fc epsilon RI alpha gene : binding of Sp1 to -315C and of a high mobility group-related molecule to -315T. (2008)
  • Author(s): Kanada S., N.Nakano, D.P.Potaczek, K.Maeda, N.Shimokawa, Y.Niwa, T.Fukai, M.Sanak, A.Szczeklik, H.Yagita, K.Okumura, H.Ogawa, C.Nishiyama
  • Journal Title: J Immunol 180 Pages: 8204-8210
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