Analyses of immune tolerance mechanism in allogeneic transplantation

• Project/Area Number: 15K09493
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: University of Tsukuba
• Principal Investigator: Nishikii Hidekazu 筑波大学, 医学医療系, 助教 (30512834)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 骨髄移植 / 制御性T細胞 / 移植片対宿主病 / TNFRSF25 / 造血幹細胞ニッチ

Outline of Final Research Achievements

Regulatory T cells (Treg) regulate the immune system and enhance immune tolerance after transplantation. In this study, we demonstrated that a single treatment of the agonistic antibody to DR3 to donor mice resulted in the expansion of donor derived Treg and prevented acute GVHD. Further, we comprehensively analyzed the immunophenotype of Treg after DR3 signal activation, demonstrating that DR3 activated Treg had an activated/mature phenotype. However, DR3 activation in mice with ongoing GVHD further promoted donor T cell activation/proliferation. These data suggest that the function of DR3 signaling was highly dependent on the activation status of the T cells. Our data demonstrated that DR3 signaling affects the function of Treg and T cell activation after alloantigen exposure in a time-dependent manner.

Research Products

• [Journal Article] Foxp3+ regulatory T cells maintain the bone marrow microenvironment for B cell lymphopoiesis. (2017)
  • Author(s): Pierini A, Nishikii H, Baker J, Kimura T, Kwon HS, Pan Y, Chen Y, Alvarez M, Strober W, Velardi A, Shizuru JA, Wu JY, Chiba S, Negrin RS.
  • Journal Title: Nature Communications. Volume: 8 Issue: 1 Pages: 15068-15068
  • DOI: 10.1038/ncomms15068
  • NAID: 120007129109
  • Peer Reviewed / Open Access
• [Journal Article] A PET Imaging Strategy to Visualize Activated T Cells in Acute Graft-versus-Host Disease Elicited by Allogenic Hematopoietic Cell Transplant. (2017)
  • Author(s): Ronald JA, Kim BS, Gowrishankar G, Namavari M, Alam IS, D'Souza, Nishikii H, Chuang HY, Ilovich O, Lin CF, Reeves R, Shuhendler A, Hoehne A, Chan CT, Baker J, Yaghoubi SS, VanBrocklin HF, Hawkins R, Franc BL, Jivan S, Slater JB, Verdin EF, Gao KT, Benjamin J, Negrin R, Gambhir SS.
  • Journal Title: Cancer Research Volume: 77(11) Issue: 11 Pages: 2893-2902
  • DOI: 10.1158/0008-5472.can-16-2953
  • Peer Reviewed / Open Access
• [Journal Article] Haploidentical transplantation using post-transplant high-dose cyclophosphamide for adult T-cell lymphoma after mogamulizumab treatment (2017)
  • Author(s): 日下部 学、栗田 尚樹、錦井 秀和ら
  • Journal Title: Rinsho Ketsueki Volume: 58 Issue: 5 Pages: 449-454
  • DOI: 10.11406/rinketsu.58.449
  • NAID: 130005690164
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed / Open Access
• [Journal Article] The Road Map for Megakaryopoietic Lineage from Hematopoietic Stem/Progenitor Cells. (2017)
  • Author(s): Nishikii H, Kurita N, Chiba S.
  • Journal Title: Stem Cells Translational Medicine Volume: 6(8) Issue: 8 Pages: 1661-1665
  • DOI: 10.1002/sctm.16-0490
  • NAID: 120007128846
  • Peer Reviewed / Open Access
• [Journal Article] DR3 signaling modulates the function of Foxp+ regulatory T cells and the severity of acute graft-versus host disease (2016)
  • Author(s): Nishikii H, KIm BS, Negrin RS
  • Journal Title: Blood Volume: 128 Pages: 2846-2858
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Exogenous TNFR2 activation protests from acute GVHD via host Treg cell expansion. (2016)
  • Author(s): Chopra M Biehi M, Nishikii H (21番目), Beilhack A
  • Journal Title: Journal of Experimental Medicine Volume: 213 Pages: 1881-1900
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] TNF-a priming enhances CD4+Foxp3+regulatory T cell suppressive function in murine GVHD preservation and treatment. (2016)
  • Author(s): Pierini A, Strober W, Nishikii H (５番目), Negrin RS
  • Journal Title: Blood Volume: 128 Pages: 866-871
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Regulatory T cell Immunotherapy in Immune-Mediated Disease. (2015)
  • Author(s): Pierini A, Schneidawind D, Nishikii H (Co first), Negrin RS.
  • Journal Title: Current Stem Cell Report Volume: 1 Pages: 177-186
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Treatment with agonistic DR3 antibody results in expansion of donor Tregs and reduced graft-versus-host disease. (2015)
  • Author(s): Kim BS, Nishikii H(Co first), Baker J, Pierini A, Schneidawind D, Pan Y, Beilhack A, Park CG, Negrin RS
  • Journal Title: Blood Volume: 126 Pages: 546-557
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Engraftment of Embryonic Stem Cells and Differentiated Progeny by Host Conditioning with Total Lymphoid Irradiation and Regulatory T Cells. (2015)
  • Author(s): Pan Y, Leverson-Gower DB, De Almeida PE, Pierini A, Baker J, Florek M, Nishikii H, Kim BS, Ke R, Wu JC, Negrin RS
  • Journal Title: Cell Reports Volume: 10 Pages: 1793-1802
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Donor requierements for regulatory T cell suppression of murine graft-versus-host disease. (2015)
  • Author(s): 3.Pierini A, Colonna L, Alvarez M, Schneidawind D, Nishikii H, BakerJ, Pan Y, Florek M, Kim BS, Negrin RS
  • Journal Title: Journal of Immunology Volume: 195 Pages: 347-355
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Foxp3陽性制御性T細胞は骨髄移植後のB細胞分化に必要な造血環境を維持している (2017)
  • Author(s): 錦井 秀和
  • Organizer: 日本造血細胞移植学会総会
  • Place of Presentation: 島根県松江市
  • Year and Date: 2017-03-02
• [Presentation] Foxp3+ 陽性制御性T細胞は骨髄移植後のB細胞分化に必要な造血環境を維持している (2017)
  • Author(s): 錦井秀和、Pierini Antonio, 横山 泰久, 木村 隆治, Hye-Sook Kwon, Maite Alvarez, Judith A Shizuru, Joy Y Wu, 千葉 滋, Robert S. Negrin.
  • Organizer: 日本造血細胞移植学会
• [Presentation] Foxp3+ Regulatory T Cells Maintain Bone Marrow Microenvironment for B Cell Differentiation From Hematopoietic Stem Cells. (2016)
  • Author(s): Nishikii Hidekazu
  • Organizer: アメリカ血液学会
  • Place of Presentation: サンディエゴ 米国
  • Year and Date: 2016-12-03
  • Int'l Joint Research
• [Presentation] Foxp3+ Regulatory T Cells Maintain Bone Marrow Microenvironment for B Cell Differentiation。 (2016)
  • Author(s): 錦井 秀和
  • Organizer: 日本血液学会総会
  • Place of Presentation: 神奈川県横浜市
  • Year and Date: 2016-10-13
• [Presentation] Foxp3+ Regulatory T Cells Maintain Bone Marrow Microenvironment for B Cell Differentiation From Hematopoietic Stem Cells. (2016)
  • Author(s): Nishikii Hidekazu
  • Organizer: JSH国際シンポジウム
  • Place of Presentation: 兵庫県淡路島
  • Year and Date: 2016-05-13
  • Int'l Joint Research
• [Presentation] Foxp3+ Regulatory T Cells Maintain Bone Marrow Microenvironment for B Cell Differentiation From Hematopoietic Stem Cells. (2016)
  • Author(s): Nishikii Hidekazu
  • Organizer: Hematopoietic Stem Cell Researchers symposium
  • Place of Presentation: 東京都港区 東京大学医科学研究所
  • Int'l Joint Research / Invited
• [Presentation] Expanded CD4+Foxp3+ regulatory T cells through DR3 signaling showed distinct immunophenotype and prevented the lethal acute-graft and host disease after allogeneic transplantation. (2015)
  • Author(s): Hidekazu Nishikii, Byung Su Kim, Antonio Pierini, Jeanette Baker, Yasuhisa Yokoyama, Dominik Schneidawind, Yuqiong Pan, Maite Alvarez, Yan Chen, Shigeru Chiba, Robert S. Negrin
  • Organizer: ASH annual meeting 2015
  • Place of Presentation: 米国 オーランド
  • Year and Date: 2015-12-05
  • Int'l Joint Research
• [Remarks] 注目の研究
  • URL: http://www.tsukuba.ac.jp/attention-research/p201705091800.html