Development of the molecular targeted therapy for the chronic rejection after renal transplantation that control immunological memory

• Project/Area Number: 26670575
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: University of Tsukuba
• Principal Investigator: SHIBUYA Kazuko 筑波大学, 医学医療系, 准教授 (00302406)
• Project Period (FY): 2014-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫系受容体 / 慢性拒絶反応 / 腎移植 / 免疫記憶 / 分子標的療法 / 拒絶反応 / 抗体療法 / 腎臓移植

Outline of Final Research Achievements

For the prevention of the chronic rejection after renal transplantation, the polypharmacy of the immunosuppressive drug for a long term is provided. However, the long-term dosage of the immunosuppressive drugs results in the immunodeficiency.
It is known that chronic inflammation induced by the alloantigen-specific memory T cells is one of the causes of the chronic rejection. Here, we show that DNAM-1 plays an important role in generation of alloantigen-specific memory of immunity by using DNAM-1-deficient mice. Moreover, we observed that fibrosis of the kidney after renal transplantation was much milder in DNAM-1-deficient mice compared with those in wild-type mice. These results suggest that DNAM-1 might be a good molecular target for prevention of the chronic rejection after the renal transplantation.

Research Products

• [Journal Article] Increased soluble CD155 in the serum of cancer patients (2016)
  • Author(s): Iguchi-Manaka A, Okumura G, Kojima H, Cho Y, Hirochika R, Bando H, Sato T, Yoshikawa H, Hara H, Shibuya A, Shibuya K.
  • Journal Title: PLoS One Volume: 11(4) Issue: 4 Pages: 1-12
  • DOI: 10.1371/journal.pone.0152982
  • NAID: 120007135543
  • Peer Reviewed / Open Access
• [Journal Article] Apoptotic epithelial cells control the abundance of Treg cells at barrier surfaces (2016)
  • Author(s): Nakahashi-Oda C, Udayanga KGS, Nakamura Y, Nakazawa Y, Miki H, Iino S, Tahara-Hanaoka S, Shibuya K, Shibuya A.
  • Journal Title: Nature Immunol, 17(4):441-453, 2016 Volume: 17 Issue: 4 Pages: 441-453
  • DOI: 10.1038/ni.3345
  • Peer Reviewed / Open Access
• [Journal Article] Expression of DNAM-1 (CD226) on inflammatory monocytes (2015)
  • Author(s): Vo AV, Takenaka E, Shibuya A, Shibuya K.
  • Journal Title: Mol Immunol Volume: 69 Pages: 70-76
  • DOI: 10.1016/j.molimm.2015.11.009
  • NAID: 120007129692
  • Peer Reviewed / Open Access
• [Journal Article] IgM-Dependent Phagocytosis in Microglia Is Mediated by Complement Receptor 3, Not Fcα/μ Receptor (2015)
  • Author(s): Weinstein JR, Quan Y, Hanson JF, Colonna L, Iorga M, Honda S, Shibuya K, Shibuya A, Elkon KB, Möller T.
  • Journal Title: J Immunol Volume: 195(11) Issue: 11 Pages: 5309-5317
  • DOI: 10.4049/jimmunol.1401195
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] CD155 (PVR/Necl5) Mediates a Costimulatory Signal in CD4+ T Cells and Regulates Allergic Inflammation (2015)
  • Author(s): 4.Yamashita--Kanemaru Y, Takahashi Y, Wang Y, Tahara-Hanaoka S, Honda S, Bernhardt G, Shibuya A, Shibuya K.
  • Journal Title: J Immunol, 194(12):5644-5653, 2015 Volume: 194 Issue: 12 Pages: 5644-5653
  • DOI: 10.4049/jimmunol.1401942
  • Peer Reviewed / Open Access
• [Journal Article] CD155 (PVR/Necl5) mediates a costimulatory signal in CD4+ T cells and regulates allergic inflammations. (2015)
  • Author(s): Yamashita Y, Takahashi Y, Wang Y, Tahara-Hanaoka S, Honda S, Bernhardt G, Shibuya A, Shibuya K.
  • Journal Title: J Immunol Volume: in press
  • Peer Reviewed
• [Journal Article] Increased CD11b+ Gr-1+ cell population in the placenta after infection with Toxoplasma gondii. (2015)
  • Author(s): Takeshima K, Sato K, Nabekura T, Nagamune K, Hamada H, Yoshikawa H, Shibuya A, Shibuya K.
  • Journal Title: Microbiol. immunol Volume: 59 Issue: 2 Pages: 95-98
  • DOI: 10.1111/1348-0421.12225
  • NAID: 120007130301
  • Peer Reviewed / Open Access
• [Journal Article] Increased CD112 expression in methylcholanthrene-induced tumors in CD155-deficient mice. (2014)
  • Author(s): Nagumo Y, Iguchi-Manaka A, Shibuya A, Shibuya K.
  • Journal Title: PLoS ONE Volume: 9(11) Issue: 11 Pages: e112415-e112415
  • DOI: 10.1371/journal.pone.0112415
  • NAID: 120007136536
  • Peer Reviewed / Open Access
• [Journal Article] Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated infammatory monocyte migration (2014)
  • Author(s): Naoya T otsuka, Yun-Gi Kim, Kazumasa Kanemaru, Kouta Niizuma, Eiji Umemoto, Kei Nagai, Satoko T ahara-Hanaoka, Chigusa Nakahasi-Oda, Shin-ichiro Honda, Masayuki Miyasaka, Kazuko Shibuya & Akira Shibuya
  • Journal Title: Nature Communications Volume: 5:4710 Issue: 1 Pages: 4710-4710
  • DOI: 10.1038/ncomms5710
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Serum under-O-glycosylated IgA1 level is not correlated with glomerular IgA deposition based upon heterogeneity in the composition of immune complexes in IgA nephropathy. (2014)
  • Author(s): Satake K, Shimizu Y, Sasaki Y, Yanagawa H, Suzuki H, Suzuki Y, Horikoshi S, Honda S, Shibuya K, Shibuya A, Tomino Y.
  • Journal Title: BMC Nephrology Volume: 15:89 Issue: 1 Pages: 89-89
  • DOI: 10.1186/1471-2369-15-89
  • Peer Reviewed / Open Access
• [Presentation] Expression of DNAM-1 (CD226) on inflammatory monocytes (2016)
  • Author(s): Vo AV, Takenaka E, Shibuya A, Shibuya K.
  • Organizer: The 55th Midwinter Conference of Immunologists
  • Place of Presentation: Asilomar Conference Grounds, Pacific Grove California, (USA)
  • Year and Date: 2016-01-23
  • Int'l Joint Research
• [Presentation] Increased soluble CD155 in patients with various cancers (2015)
  • Author(s): guchi-Manaka A, Shibuya A, Shibuya K
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2015-11-18
• [Presentation] Involvement of DNAM-1 (CD226) expressed on small peritoneal macrophages in antigen presentation (2015)
  • Author(s): Takenaka E, Vo AV, Shibuya A, Shibuya K
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2015-11-18
• [Presentation] Development of a novel method for isolation of follicular dendritic cells (2015)
  • Author(s): Sato K, Honda S, Shibuya K, Shibuya A
  • Organizer: 第44回日本免疫学会総会・学術集会
  • Place of Presentation: 札幌コンベンションセンター（札幌）
  • Year and Date: 2015-11-18
• [Presentation] The role of DNAM-1 and CD155 in tumor immunity and escape (2015)
  • Author(s): Shibuya K, Iguchi-Manaka A, Kojima H, Cho Y, Hirochika R, Shibuya A
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Oarai (Japan)
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] Apoptotic epithelial cells control regulatory T cell expansion (2015)
  • Author(s): Nakahashi-Oda C, Udayanga K G S, Nakamura Y, Nakazawa Y, Totsuka N, Miki H, Iino S, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Oarai (Japan)
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] Marginal zone B cells exacerbate endotoxic shock via interleukin-6 secretion induced by Fcα/μR-coupled TLR4 signaling (2015)
  • Author(s): Honda S, Sato K, Totsuka N, Fujiyama S, Fujimoto M, Miyake K, Nakahashi-Oda C, Tahara-Hanaoka S, Honda S, Shibuya K, Shibuya A.
  • Organizer: International Symposium on Immune Regulation
  • Place of Presentation: Oarai Park Hotel, Oarai (Japan)
  • Year and Date: 2015-10-29
  • Int'l Joint Research
• [Presentation] Increased soluble CD155 in the serum of cancer patients (2015)
  • Author(s): Iguchi-Manaka A, Hiroshi Kojima, Cho Y, Shibuya A, Shibuya K.
  • Organizer: 第74回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場（名古屋）
  • Year and Date: 2015-10-08
• [Presentation] 癌患者血清における可溶型CD155の上昇 (2015)
  • Author(s): 井口研子、渋谷彰、渋谷和子
  • Organizer: 第7回血液疾患免疫療法研究会学術集会
  • Place of Presentation: 東京大学 伊藤国際学術研究センター（東京）
  • Year and Date: 2015-09-26
• [Presentation] 免疫監視と免疫逃避におけるポリオウイルスレセプターの役割 (2015)
  • Author(s): 渋谷 和子
  • Organizer: 東北大学加齢医学研究所セミナー
  • Place of Presentation: 東北大学加齢医学研究所（仙台）
  • Year and Date: 2015-03-23
  • Invited
• [Presentation] Critical role of DNAM-1 in acute and chronic allograft rejection. (2015)
  • Author(s): 阿部 史枝、渋谷 和子、渋谷 彰
  • Organizer: 第3回筑波大学・東京理科大学生命医科学研究所合同リトリート
  • Place of Presentation: 東京理科大学セミナーハウス（野田）
  • Year and Date: 2015-03-20
• [Presentation] Soluble CD155 is involved in the escape from tumor immunity. (2015)
  • Author(s): 井口 研子、渋谷 彰、渋谷 和子
  • Organizer: 第3回筑波大学・東京理科大学生命医科学研究所合同リトリート
  • Place of Presentation: 東京理科大学セミナーハウス（野田）
  • Year and Date: 2015-03-20
• [Presentation] Soluble CD155 is involved in the escape from tumor immunity. (2015)
  • Author(s): Iguchi-Manaka A, Shibuya A, Shibuya K.
  • Organizer: 第5回新学術発がんスパイラル国際シンポジウム
  • Place of Presentation: 神戸ポートピアホテル（神戸）
  • Year and Date: 2015-02-26
• [Presentation] DNAM-1 (CD226) plays an important role in antigen presentation by small peritoneal macrophages. (2015)
  • Author(s): Takenaka E, Shibuya A, Shibuya K.
  • Organizer: 第5回新学術発がんスパイラル国際シンポジウム
  • Place of Presentation: 神戸ポートピアホテル（神戸）
  • Year and Date: 2015-02-26
• [Presentation] DNAM-1 (CD226) plays an important role in antigen presentation by small peritoneal macrophages. (2014)
  • Author(s): Takenaka E, Shibuya A, Shibuya K.
  • Organizer: 第43 回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-11
• [Presentation] Soluble CD155 is involved in the escape from tumor immunity. (2014)
  • Author(s): Iguchi-Manaka A, Shibuya A, Shibuya K.
  • Organizer: 第43 回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10 – 2014-12-12
• [Presentation] Toll-like receptor 4 and MAIR-II/CLM-4/LMIR2 immunoreceptor regulate VLA-4-mediated inflammatory monocyte migration. (2014)
  • Author(s): Totsuka N, Kim YG, Kanemaru K, Niizuma K, Umemoto E, Nagai K, Tahara-Hanaoka S, Nakahashi-Oda C, Honda S, Miyasaka M, Shibuya K, Shibuya A.
  • Organizer: 第43 回日本免疫学会総会・学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-12-10
• [Presentation] CD155 regulates regulatory T cell population and attenuates acute graft-versus-host disease. (2014)
  • Author(s): Kanaya M, Shibuya K, Abe F, Teshima T, Shibuya A.
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪）
  • Year and Date: 2014-10-31
• [Presentation] 免疫システムの人為的制御と疾患の克服 (2014)
  • Author(s): 渋谷 和子
  • Organizer: 第46回日本医学教育学会大会
  • Place of Presentation: 和歌山県立医科大学（和歌山）
  • Year and Date: 2014-07-18
• [Presentation] 可溶型ポリオウイルスレセプター（CD155)によるがん免疫逃避 (2014)
  • Author(s): 渋谷 和子
  • Organizer: 第26回千葉基礎・臨床免疫セミナー
  • Place of Presentation: 千葉大亥鼻イノベーションプラザ（千葉）
  • Year and Date: 2014-05-22
  • Invited
• [Presentation] 腫瘍免役逃避機構における可溶型CD155の役割 (2014)
  • Author(s): 井口 研子、清松 裕子、池田 達彦、坂東 裕子、渋谷 彰、渋谷 和子、原 尚人
  • Organizer: 第114回日本外科学会定期学術集会
  • Place of Presentation: 国立京都国際会館（京都）
  • Year and Date: 2014-04-03 – 2014-04-05
• [Remarks] 免疫学研究室ホームページ
  • URL: http://immuno-tsukuba.com/index.html
• [Remarks] つくばリポジトリ
  • URL: https://tsukuba.repo.nii.ac.jp/index.php?action=pages_view_main&active_action=repository_view_main_item_snippet&index_id=987&pn=1&count=20&order=7&lang=japanese&page_id=13&block_id=83
• [Remarks] TRIOS
  • URL: http://trios.tsukuba.ac.jp/researcher/0000001639
• [Patent(Industrial Property Rights)] 可溶型CD155タンパク質を用いた癌の検出方法 (2015)
  • Inventor(s): 渋谷彰、渋谷和子、井口研子
  • Industrial Property Rights Holder: 渋谷彰、渋谷和子、井口研子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-01-26
  • Acquisition Date: 2015-07-27
• [Patent(Industrial Property Rights)] 可溶型CD155タンパク質を用いた癌の検出方法 (2015)
  • Inventor(s): 渋谷 彰、渋谷 和子、井口 研子
  • Industrial Property Rights Holder: 渋谷 彰、渋谷 和子、井口 研子
  • Industrial Property Rights Type: 特許
  • Filing Date: 2015-01-26