Low-dose IL-2 combined with PD-1 blockade separates GVHD and GVL effect.

• Project/Area Number: 26461449
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Okayama University
• Principal Investigator: Ken-ichi Matsuoka 岡山大学, 大学病院, 講師 (90432640)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 造血幹細胞移植 / 制御性T細胞 / GVHD / 免疫寛容 / 橋渡し研究 / 移植片対宿主病 / 血液内科学 / 造血幹細胞移植学

Outline of Final Research Achievements

We previously reported that low-dose IL-2 can induce immune-tolerance with the increase of Treg. However, Treg increase might reduce GVL effect. Therefor, we need to develop the technique to regulate Treg homeostasis during low-dose IL-2 therapy. In this study, our murine study and human subject analysis clearly demonstrated that PD-1 signaling has indispensable role for Treg homeostasis during IL-2. Our results might provide important information for the development of the Treg-based immune therapy for patients after HSCT.

Research Products

• [Journal Article] PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy. (2017)
  • Author(s): Asano T, Meguri Y, Yoshioka T, Kishi Y, Iwamoto M, Nakamura M, Sando Y, Yagita H, Koreth J, Kim HT, Alyea EP, Armand P, Cutler CS, Ho VT, Antin JH, Soiffer RJ, Maeda Y, Tanimoto M, Ritz J, Matsuoka KI.
  • Journal Title: Blood Volume: 129 Issue: 15 Pages: 2186-2197
  • DOI: 10.1182/blood-2016-09-741629
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Treatment of thrombotic microangiopathy after hematopoietic stem cell transplantation with recombinant human soluble thrombomodulin (2016)
  • Author(s): Fujiwara H, Maeda Y, Sando Y, Nakamura M, Tani K, Ishikawa T, Nishimori H, Matsuoka K, Fujii N, Kondo E, Tanimoto M.
  • Journal Title: Transfusion Volume: 56 Issue: 4 Pages: 886-92
  • DOI: 10.1111/trf.13437
  • Peer Reviewed
• [Journal Article] Vigorous inflammatory responses in noninfectious pulmonary complication induced by donor lymphocyte infusion. (2016)
  • Author(s): Nishie M, Fujii N, Mimura Y, Asano T, Mimura-Kimura Y, Aoe K, Aoe M, Nakashima H, Fujiwara H, Nishimori H, Matsuoka K, Kondo E, Maeda Y, Tanimoto M.
  • Journal Title: Transfusion Volume: 56 Issue: 1 Pages: 231-6
  • DOI: 10.1111/trf.13283
  • Peer Reviewed
• [Journal Article] Anti-IL-12/23 p40 antibody attenuates experimental chronic graft-versus-host disease via suppression of IFN-γ/IL-17-producing cells. (2015)
  • Author(s): Okamoto S, Fujiwara H et al.
  • Journal Title: The Journal of Immunology Volume: 194 Issue: 3 Pages: 13571363-13571363
  • DOI: 10.4049/jimmunol.1400973
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] 急性リンパ性白血病に対するCAR細胞療法の新たな展開 (2014)
  • Author(s): 松岡 賢市
  • Journal Title: 血液内科 Volume: 69(5) Pages: 652-657
• [Journal Article] リンハ腫治療におけるPD-1阻害 (2014)
  • Author(s): 松岡 賢市
  • Journal Title: 腫瘍内科 Volume: 14(5) Pages: 455-462
• [Journal Article] Programmed Death-1 Pathway in Host Tissues Ameliorates Th17/Th1-Mediated Experimental Chronic Graft-versus-Host Disease (2014)
  • Author(s): Hideaki Fujiwara, Yoshinobu Maeda et al.
  • Journal Title: The Journal of Immunology Volume: 193 Issue: 5 Pages: 25652573-25652573
  • DOI: 10.4049/jimmunol.1400954
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Exploring regulatory T cell-based therapy for refractory graft-versus-host disease (2014)
  • Author(s): Ken-ichi Matsuoka
  • Journal Title: Rinsho Ketsueki Volume: 55(6) Pages: 670-81
  • NAID: 130004501867
  • Peer Reviewed
• [Journal Article] Increased mitochondrial apoptotic priming of human regulatory T cells after allogeneic hematopoietic stem cell transplantation. (2014)
  • Author(s): Murase K, Kim HT, Bascug OR, Kawano Y, Ryan J, Matsuoka K, Davids MS, Koreth J, Ho VT, Cutler C, Armand P, Alyea EP, Blazar BR, Antin JH, Soiffer RJ, Letai A, Ritz J.
  • Journal Title: Haematologica Volume: 99(9) Issue: 9 Pages: 1499-508
  • DOI: 10.3324/haematol.2014.104166
  • Peer Reviewed
• [Presentation] PD-1 signaling has a critical role in maintaining Regulatory T Cell Homeostasis; Implication for Treg depletion therapy by PD-1 Blockade (2015)
  • Author(s): Takeru Asano, Ken-ichi Matsuoka
  • Organizer: American Society of Hematology
  • Place of Presentation: オーランド
  • Year and Date: 2015-12-08
  • Int'l Joint Research
• [Presentation] Role of Regulatory T cells in Hematopoietic Stem Cell Transplantation (2015)
  • Author(s): Ken-ichi Matsuoka
  • Organizer: 台湾血液学会
  • Place of Presentation: 台北市
  • Year and Date: 2015-04-15
  • Int'l Joint Research / Invited
• [Presentation] ～造血幹細胞移植を可視化する～ 移植後免疫再構築の基本的枠組みについて (2015)
  • Author(s): 松岡 賢市
  • Organizer: 日本血液学会中国四国地方会教育セミナー
  • Place of Presentation: 鳥取県鳥取市
  • Year and Date: 2015-03-13
• [Presentation] 造血幹細胞移植に関わる免疫学 ～免疫システムを安全に入れ替えたい～ (2015)
  • Author(s): 松岡 賢市
  • Organizer: 第４回 岡山フローサイトメトリー研究会
  • Place of Presentation: 岡山県岡山市
  • Year and Date: 2015-02-21
• [Presentation] Enhanced expression of PD-1 modulates CD4+Foxp3+ regulatory T cell homeostasis during low-dose IL-2 therapy in patients with chronic Graft-versus-Host disease (2014)
  • Author(s): Takeru Asano, Haesook T. Kim, John Koreth, Robert Soiffer, Yusuke Meguri, Takanori Yoshioka, Hideo Yagita, Mitune Tanimoto, MD, PhD, Jerome Ritz, MD and Ken-ichi Matsuoka
  • Organizer: 56th ASH Annual Meeting & Exposition
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-08 – 2014-12-12
• [Presentation] Host immune status determines the effects of therapeutic Interleukin-2 administration: Enhancement of GVL or Induction of Tolerance? (2014)
  • Author(s): Yusuke Meguri, Takeru Asano, Takanori Yoshioka, Haruka Izumi, Yuriko Kishi, Yoshinobu Maeda, Mitune Tanimoto, and Ken-ichi Matsuoka
  • Organizer: 56th ASH Annual Meeting & Exposition
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-08 – 2014-12-12
• [Presentation] Early Homeostatic Expansion of Regulatory T Cells with the Predominant Effector/Memory Phenotype May Stabilize Immune Recovery in the First Month after HSCT (2014)
  • Author(s): Takanori Yoshioka, Yusuke Meguri, Takeru Asano, Taro Masunari, Kumiko Kagawa, Koichi Nakase, Yoshinobu Maeda, Mitsune Tanimoto, and Ken-ichi Matsuoka
  • Organizer: 56th ASH Annual Meeting & Exposition
  • Place of Presentation: San Francisco
  • Year and Date: 2014-12-08 – 2014-12-12
• [Presentation] 造血幹細胞移植における制御性T細胞の役割 (2014)
  • Author(s): 松岡 賢市
  • Organizer: 血液科学セミナー
  • Place of Presentation: 東京都
  • Year and Date: 2014-11-09
• [Presentation] Rapid Assessment of Low-dose IL-2 Administration on Foxp3+ Regulatory T cell Homeostasis (2014)
  • Author(s): Yusuke Meguri, Ken-ichi Matsuoka, Takeru Asano, Takanori Yoshioka, Haruka Izumi Yuriko Kishi and Mitsune Tanimoto
  • Organizer: 第76回 日本血液学会総会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] Early homeostatic expansion of regulatory T cells after HSCT is susceptible to environmental factors (2014)
  • Author(s): Takanori Yoshioka, Ken-ichi Matsuoka, Yusuke Meguri, Takeru Asano, Yuriko Kishi, Taiga Kuroi, Tatsunori Ishikawa, Kyosuke Saeki, Eiko Hasegawa, Yoshikazu Yamamoto, Katsuma Tani, Yasuhiro Shiote, Nobuharu Fujii, Eisei Kondo, Yoshinobu Maeda, Taro Masunari, Kumiko Kagawa, Koichi Nakase and Mitsune Tanimoto
  • Organizer: 第76回 日本血液学会総会
  • Place of Presentation: 大阪府大阪市
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 低用量インターロイキン-2療法は慢性移植片対宿主病患者において制御性T細胞のホメオスタシスを回復させる (2014)
  • Author(s): 松岡 賢市
  • Organizer: 第２回 血液学アカデミー
  • Place of Presentation: 京都府京都市
  • Year and Date: 2014-09-20
• [Presentation] 制御性T細胞をめぐるヒトとマウスの「あいだ」 (2014)
  • Author(s): 松岡 賢市
  • Organizer: 第18回 血液三都物語若手の会
  • Place of Presentation: 兵庫県神戸市
  • Year and Date: 2014-07-19
• [Presentation] Rapid Assessment of Low-dose IL-2 Administration on Foxp3+ Regulatory T cell Homeostasis (2014)
  • Author(s): Yusuke Meguri, Ken-ichi Matsuoka, Takeru Asano, Takanori Yoshioka, Haruka Izumi and Mitsune Tanimoto
  • Organizer: 日本血液学会国際シンポジウム
  • Place of Presentation: 静岡県浜松市
  • Year and Date: 2014-05-25 – 2014-05-26