Analyses of Regulatory Mechanisms in Oral Immune Responses and Development of a New Immunotherapy Targeting Dendritic Cells

2010 Fiscal Year Final Research Report

• Project/Area Number: 20249075
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pathobiological dentistry/Dental radiology
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: AZUMA Miyuki Tokyo Medical and Dental University, 大学院・医歯学総合研究科, 教授 (90255654)
• Co-Investigator(Kenkyū-buntansha): HASHIGUCHI Masaaki 東京医科歯科大学, 大学院・医歯学総合研究科, 助教 (20372443) ; HASE Hidenori 東京医科歯科大学, 大学院・医歯学総合研究科, 准教授 (70332997)
• Project Period (FY): 2008 – 2010
• Keywords: 免疫 / 感染 / 炎症

Research Abstract

Migrating dendritic cells (DC) from oral mucosa into regional lymph nodes were divided into four subsets similar to cutaneous migrating DCs. CD207-CD11c^<hi> F1-DCs that migrated quickly, expressed the highest levels of co-signal molecules, whereas CD207+CD11c^<int/lo> F3-DCs that migrated at the later time point were further divided into both CD103+CD207+ submucosal DCs and CD103- Langerhans cells (LCs) and the latter expressed the lowest co-signal molecules, suggest tolerogenic properties. We demonstrated that using mouse skin allergic models, silencing of CD86 co-signal molecule in skin DCs by RNA interference efficiently inhibited both early innate immune responses at the local site and adaptive immune responses in the secondary lymphoid tissues.

Research Products

• [Journal Article] B7-H1 overexpression regulates epithelial-mesenchymal transition and accelerates carcinogenesis in skin. (2011)
  • Author(s): Cao Y, Zhang L, Kamimura Y, Ritprajak P, Hashiguchi M, Hirose S, Azuma M
  • Journal Title: Cancer Res. 71(4) Pages: 1235-1243
  • Peer Reviewed
• [Journal Article] PD-1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft. (2010)
  • Author(s): Morita M, Fujino M, Jiang G, Kitazawa Y, Xie L, Azuma M, Yagita H, Nagao S, Sugioka A, Kurosawa Y, Takahara S, Fung J, Qian S, Lu L, Li X
  • Journal Title: Am J Transplant 10 Pages: 40-46
  • Peer Reviewed
• [Journal Article] Topical application of siRNA targeting cutaneous dendritic cells in allergic skin disease. (2010)
  • Author(s): Azuma M, Ritprajak P, Hashiguchi M
  • Journal Title: Methods Mol Biol 623 Pages: 373-81
  • Peer Reviewed
• [Journal Article] Keratinocytes-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses. (2010)
  • Author(s): itprajak P, Hashiguchi M, Tsushima F, Chalermsarp N, Azuma M
  • Journal Title: J.Immunol. 184 Pages: 4818-4925
  • Peer Reviewed
• [Journal Article] Enhancement of effector CD8+ T cell function by tumour-associated B7-H3 and modulation of its counter receptor triggering receptor expressed on myeloid cell-like transcripts 2 (TLT-2) at tumor sites. (2010)
  • Author(s): Kobori H, Hashiguchi M, Piao J, Kato M, Ritprajak P, Azuma M
  • Journal Title: Immunology 130(3) Pages: 363-373
  • Peer Reviewed
• [Journal Article] CD4 T-cell help programs a change in CD8 T-cell function enabling effective long-term control of murine gammherpesvirus 68 : role of PD-1-PD-L1 interactions. (2010)
  • Author(s): Dias P, Giannoni F, Lee LN, Han D, Yoon S, Yagita H, Azuma M, Sarawar SR
  • Journal Title: J Virol 84(16) Pages: 8241-8249
  • Peer Reviewed
• [Journal Article] Crucial roles of B7-H1 and B7-DC expressed on mesenteric lymph node dendritic cells in the generation of antigen-specific CD4+Foxp3+ regulatory T cells in the establishment of oral tolerance. (2010)
  • Author(s): T Fukaya, H Takagi, Y Sato, K Sato, K Eizumi, H Taya, T Shin, L Chen, C Dong, M Azuma, H Yagita, B Malissen, K Sato
  • Journal Title: Blood. 116(13) Pages: 2266-2276
  • Peer Reviewed
• [Journal Article] GITR ligand-mediated local expansion of regulatory T cells contributes to immune privilege of corneal allografts. (2010)
  • Author(s): J Hori, Taniguchi H, Eang M, Oshima M, Azuma M
  • Journal Title: Invest Ophthalmol Vis Sci 51(21) Pages: 6556-6565
  • Peer Reviewed
• [Journal Article] Role of the glucocorticoid-induced TNFR-related protein (GITR)-GITR ligand pathway in innate and adaptive immunity. (2010)
  • Author(s): Azuma M
  • Journal Title: Cri Rev Immunol. 30(6) Pages: 457-457
  • Peer Reviewed
• [Journal Article] In vivo fu nction of immune inhibiotory molecule B7-H4 in a murine vascularized model of cardiac transplantation. (2010)
  • Author(s): Yamaura K, Watanabe T, Boenisch O, Yeung M, Yang S, Magee C, Padera R, Datta S, Schtton T, Kamimura Y, Azuma M, Najafian N
  • Journal Title: American J Transplant 10(10) Pages: 2355-2362
  • Peer Reviewed
• [Journal Article] Identification of three distinct subsets of migrating dendritic cells from oral mucosa within the regional lymph nodes. (2009)
  • Author(s): Chalermsarp N, Azuma M
  • Journal Title: Immunology 127 Pages: 558-566
  • Peer Reviewed
• [Journal Article] Enhancement of T cell-mediated anti-tumor immunity via the ectopically expressed glucocruticoid-induced tumor necrosis factor receptor-related receptor ligand on tumors. (2009)
  • Author(s): Piao J, Kamimura Y, Iwai H, Cao Y, Kikuchi K, Hashiguchi M, Masunaga T, Jiang H, Tamura K, Sakaguchi S. Azuma M
  • Journal Title: Immunology 127 Pages: 489-499
  • Peer Reviewed
• [Journal Article] The Glucocorticoid-induced TNFR-related protein (GITR)-GITR ligand pathway acts as a mediator of cutaneous dendritic cell migration and promotes T-cell mediated acquired immunity. (2009)
  • Author(s): Kamimura Y, Iwai H, Piao J, Hashiguchi M, Azuma M
  • Journal Title: J Immunol 182 Pages: 2708-2716
  • Peer Reviewed
• [Journal Article] PD-1/PD-L blockade prevents anergy induction and enhances the anti -tumor activities of glycolipid -activated invariant NKT cells. (2009)
  • Author(s): Parekh VV, Lalani S, Kim S, Halder R, Azuma M, Yagira H, Kumar V, Van Kaer L
  • Journal Title: J Immunol 182 Pages: 2816-2826
  • Peer Reviewed
• [Journal Article] Possible involvement of soluble B7-H4 in T-cell-mediated inflammatory immune responses. (2009)
  • Author(s): Kamimura Y, kobori H, Piao J, Hashiguchi M, Matsumoto K, Horose S, Azuma M
  • Journal Title: Biochem Biophys Res Commun 389 Pages: 349-353
  • Peer Reviewed
• [Journal Article] PD-1-PD-L1 interactions promote tolerance by blocking the T cell receptor stop signal. (2009)
  • Author(s): Fife BT, Eagar TN, Pauken KE, Wu J, Obu T, Tang Q, Azuma M, Krummel MF, Bluestone JA
  • Journal Title: Nature Immunol 10 Pages: 1185-1193
  • Peer Reviewed
• [Journal Article] Impaired CD4 and CD8 effector function and decreased memory T cell populations in ICOS-deficient patients. (2009)
  • Author(s): Takahashi N, Matsumoto K, Saito H, Nanki T, Miyasaka N, Kobata T, Azuma M, Lee S, Mizutani S, Morio T
  • Journal Title: J Immunol 182 Pages: 5515-5527
  • Peer Reviewed
• [Journal Article] Expression of IFN-γ before and after treatment of oral lichen planus with 0.1% fluocinolone acetonide in orabese. (2009)
  • Author(s): Youngnak-Piboonratnakit P, Dhaunuthai K, Thongprasom K, Luckprom P, Sarideechighu W, Luangjarmekorn L, Azuma M
  • Journal Title: J Oral Pathol Med 38(9) Pages: 689-694
  • Peer Reviewed
• [Journal Article] Topical application of cream-emulsified CD86 siRNA ameliorates allerg ic skin disease by targeting cutaneous dendritic cells. (2008)
  • Author(s): Ritprajak P, Hashiguchi M, Azuma M
  • Journal Title: Mol Ther 16(7) Pages: 1323-1330
  • Peer Reviewed
• [Journal Article] GITR ligand-costimulation activates effector and regulatory functions of CD4+ T cells. (2008)
  • Author(s): Igarashi H, Cao Y, Iwai H, Piao J, Kamimura Y, Hashiguchi M, Amagasa T. Azuma M
  • Journal Title: Biochem Biophys Res Commun 369 Pages: 1134-1138
  • Peer Reviewed
• [Journal Article] B7-DC induced by IL-13 works as a feed back regulator in the effector phase of allergic asthuma. (2008)
  • Author(s): Matsumoto K, Fukuyama S, Eguchi-Tsuda M, Nakano T, Matsymoto T, Matsumura M, Moriwaki A, Kan-o K, Wada Y, Yagita H, Shin T, Pardoll DM, Patcharee R, Azuma M, Nakanishi Y, Inoue H
  • Journal Title: Biochem Biophys Res Commun 365 Pages: 170-175
  • Peer Reviewed
• [Journal Article] Trigerring receptor expressed on myeloid cell-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses. (2008)
  • Author(s): Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Kozono H, Azuma M
  • Journal Title: Proc.Nathl.Acad.Sci.USA 105 Pages: 10495-10500
  • Peer Reviewed
• [Journal Article] Mini-review; Immunoregulatory molecules B7-H1 (CD274) contributes to skin carcinogenesis.
  • Author(s): Cao Y, Zhang L, Ritprajak P, Tsushima F, Youngnak-Piboonratanakit P, Kamimura Y, Hashiguchi M, Azuma M
  • Journal Title: Cancer Res. in press
  • Peer Reviewed
• [Presentation] Comparative studies on migrating DCs from oral mucosal versus skin in the regional lymph nodes-Phenotypic properties in three distinct subsets. (2010)
  • Author(s): Aramaki O, Chalermsarp N, Kamimura Y, Hase H, Otsuki M, Tagami J, Azuma M
  • Organizer: DC2010 : Forum on Vaccine Science
  • Place of Presentation: Lugano, Switzerland
  • Year and Date: 20100926-20100930
• [Presentation] The GITR-GITR ligand pathway acts as a mediator of cutaneous DC migration and promotes T cell-mediated immunity. (2010)
  • Author(s): Azuma M, Piao J, Kamimura Y
  • Organizer: DC2010 : Forum on Vaccine Science
  • Place of Presentation: Lugano, Switzerland
  • Year and Date: 20100926-20100930
• [Presentation] B7-H1 on epidermal keratinocytes downregulates skin inflammation, but promotes squamous cell carcinoma formation. (2010)
  • Author(s): Cao Y, Zhang L, Ritprajak P, Hashiguchi M, Hase H, Azuma M
  • Organizer: 第69回日本癌学会学術総会
  • Place of Presentation: 大阪
  • Year and Date: 20100922-20100924
• [Presentation] マウス臼歯切削後の所属リンパ節における免疫機能分子の解析 (2010)
  • Author(s): 荒牧音、大槻昌幸、田上順次、東みゆき
  • Organizer: 第52回歯科基礎医学会
  • Place of Presentation: 東京
  • Year and Date: 20100920-20100922
• [Presentation] Identification of three distinct subsets of migrating dendritic cells from oral mucosa within the regional lymph nodes. (2010)
  • Author(s): Chalermsarp N, Aramaki O, Azuma M
  • Organizer: 14th International Congress of Immunology (ICI)
  • Place of Presentation: Kobe
  • Year and Date: 20100822-20100827
• [Presentation] Triggering receptor expressed on myeloid cells-like transcript 2 (TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses in mice and humans. (2010)
  • Author(s): Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Azuma M
  • Organizer: 14th ICI
  • Place of Presentation: Kobe
  • Year and Date: 20100822-20100827
• [Presentation] Impaired CD4 and CD8 Effector Function and Decreased Memory T-cell Populations in ICOS-deficient Patients. (2010)
  • Author(s): Morio T, Terada N, Nanki T, Miyasaka N, Kobata T, Matsumoto K, Azuma M, Mizutani S
  • Organizer: 14th ICI
  • Place of Presentation: Kobe
  • Year and Date: 20100822-20100827
• [Presentation] Keratinocyte-associated B7-H1 directly regulates cutaneous effector CD8+ T cell responses. (2010)
  • Author(s): Ritprajak P, Hashiguchi M, Azuma M
  • Organizer: 14th ICI
  • Place of Presentation: Kobe
  • Year and Date: 20100822-20100827
• [Presentation] Antibodies against B7-DC with differential binding properties exert opposite effects : Implication of dual functions in PD -1 and B7-DC interactions. (2010)
  • Author(s): Azuma M, Ritprajak P, Akiba H, Yagita H, Okumura K, Hashiguchi M
  • Organizer: 14th ICI
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] Overexpression of B7-H1 on epidermal keratinocytes promotes squamous cell carcinoma formation. (2010)
  • Author(s): Cao Y, Zhang L, Ritprajak P, Hashiguchi M, Azuma M
  • Organizer: 14^<th> ICI
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] Enhancement of effector CD8^+ T cell function by tumor-associated B7-H3 and modulation of its counter receptor triggering receptor expressed on myeloid cell-like transcript 2 (TLT-2) at tumor sites. (2010)
  • Author(s): Kobori H, Hashiguchi M, Azuma M
  • Organizer: 14^<th> ICI
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] The GITR-GITR ligand pathway acts as a mediator of cutaneous DC migration and promotes T cell-mediated immunity. (2010)
  • Author(s): Kamimura Y, Piao J, Hashiguchi M, Azuma M
  • Organizer: 14th ICI
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] Triggering receptor expressed on myeloid cells-like transcript 2(TLT-2) is a counter-receptor for B7-H3 and enhances T cell responses in mice and humans. (2010)
  • Author(s): Hashiguchi M, Kobori H, Ritprajak P, Kamimura Y, Azuma M
  • Organizer: 14th ICI
  • Place of Presentation: Kobe, Japan
  • Year and Date: 20100822-20100827
• [Presentation] Overexpression of B7-H1 on epidermal keratinocytes promotes squamous cell carcinoma (2010)
  • Author(s): Cao Y, Zhang L, Ritprajak P, Hashiguchi M, Azuma M
  • Organizer: 97th AAI Annual Meeting, American Association of Immunologists, Immunology 2010
  • Place of Presentation: Baltimore, USA
  • Year and Date: 20100507-20100511
• [Presentation] Tumor-infiltrating CD8^+ T cells express TLT-2, a counter receptor for B7-H3 and B7-H3-transeduced tumors preferentially augment effector function of CD8+ T cells. (2009)
  • Author(s): Kobori H, Hashiguchi M, Piao J, Azuma M
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Enhancement of T cell-mediated anti-tumor immunity via the ectopically expressed GITRL on tumors. (2009)
  • Author(s): Piao J, Kamimura Y, Hashiguchi M, Cao Y, Azuma M
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Roles of keratinocyte-associated B7-H1 in squamous cell carcinoma formation and growth of tumor cells. (2009)
  • Author(s): Cao Y, Hashiguchi M, Azuma M
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Mechanisms of effective inhibition by topical application of CD86 siRNA treatment in allergic skin disease. (2009)
  • Author(s): Kamimura Y, Ritprajak P, Hashiguchi M, Azuma M
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Binding property, expression, and function of human TLT2,a counter-receptor for B7-H3. (2009)
  • Author(s): Hashiguchi M, Kobori H, Azuma M
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Differential expression of regulatory molecules in three subsets of migrating oral mucosal DCs in regional lymph nodes. (2009)
  • Author(s): Chalermsarp N, Aramaki O, Kamimura Y, Azuma M
  • Organizer: 第39回日本免疫学会
  • Place of Presentation: 大阪
  • Year and Date: 20091202-20091204
• [Presentation] Enhancement of T-cell-mediated anti-tumor immunity via the ectopically expressed GITR ligand on tumors. (2009)
  • Author(s): Piao J, Kamimura Y, Cao Y, Hashiguchi M, Azuma M
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] Analyses of anti-tumor immunity enhanced by a B7-H3 costimulator. (2009)
  • Author(s): Kobori H, Hashiguchi M, Piao J, Azuma M
  • Organizer: 第68回日本癌学会学術総会
  • Place of Presentation: 横浜
  • Year and Date: 20091001-20091003
• [Presentation] 口腔粘膜樹状細胞による免疫制御 (2009)
  • Author(s): 東みゆき
  • Organizer: 第19回日本口腔粘膜学会シンポジウム:口腔粘膜疾患のトランスレーショナルリサーチ
  • Place of Presentation: 神奈川
  • Year and Date: 2009-06-05
• [Presentation] Identification of different subsets of oral mucosa. (2008)
  • Author(s): Chalersarp N. Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] GITR-GITRL pathway modulates migrating capacity of cutaneous DCs in the skin. (2008)
  • Author(s): Kamimura Y, Cao Y, Hashiguchi M, Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] Tumor-associated B7-H3 augments cytotoxicity of CD8+ T cells at effector phase. (2008)
  • Author(s): Kobori H, Hashiguchi M, Piao J, Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] CD28 costimulation affects both susceptibility of effector T cells to regulatory T cells and inhibitory function of Treg. (2008)
  • Author(s): Cao Y, Kamimura Y, Hashiguchi M, Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] Identification of different subsets of oral mucosal DCs in regional lymph nodes. (2008)
  • Author(s): Chalermsarp N, Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] GITRリガンド共刺激はCD4 T細胞のエフェクター機能と制御性機能の両者を活性化する (2008)
  • Author(s): Igarashi H, Cao Y, Piao J, Kamimura Y, Hashiguchi M, Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] Topical application of cream emulsified CD86 siRNA ameliorates allergic skin disease by targeting cutaneous dendritic cells. (2008)
  • Author(s): Ritprajak P, Hashiguchi M, Azuma M
  • Organizer: 第38回日本免疫学会
  • Place of Presentation: 京都
  • Year and Date: 20081201-20081203
• [Presentation] 所属リンパ節における口腔粘膜由来の異なる樹状細胞サブセットの同定 (2008)
  • Author(s): Chalermsarp N、東みゆき
  • Organizer: 第50回歯科基礎医学会
  • Place of Presentation: 東京
  • Year and Date: 20080923-20080925
• [Presentation] Phenotypic and functional analyses of dendritic cells in oral mucosa (2008)
  • Author(s): Chalermsarp N、荒牧音、東みゆき
  • Organizer: 第62回日本口腔科学会学術集会
  • Place of Presentation: 福岡
  • Year and Date: 20080417-20080418
• [Presentation] 共刺激分子を標的とする免疫制御法 (2008)
  • Author(s): 東みゆき
  • Organizer: 第62回日本口腔科学会シンポジウム2免疫制御の科学
  • Place of Presentation: 福岡
  • Year and Date: 20080407-20080408
• [Presentation] T cell costimulation and immune regulation-Application to Oral immunobiology- (2008)
  • Author(s): Azuma M
  • Organizer: Annual Meeting of Taiwan Association of Oral Pathology
  • Place of Presentation: Taipei
  • Year and Date: 2008-11-29
• [Presentation] T cell costimulation and immune regulation-Application to oral immunobiology- (2008)
  • Author(s): Azuma M
  • Organizer: 31th Annual Scientific Meeting of ADS-ROC
  • Place of Presentation: Taipei
  • Year and Date: 2008-11-28
• [Presentation] 共刺激分子による免疫寛容制御特別講演 (2008)
  • Author(s): 東みゆき
  • Organizer: 第2回肝免疫研究会
  • Place of Presentation: 松山
  • Year and Date: 2008-06-06
• [Remarks] ホームページ
  • URL: http://www.tmd.ac.jp/mim/index.html