Establishment of early and simple diagnostic method for complications and recurrence after hematopoietic stem cell transplantation

• Project/Area Number: 17K09017
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Laboratory medicine
• Research Institution: Osaka City University
• Principal Investigator: HINO MASAYUKI 大阪市立大学, 大学院医学研究科, 教授 (50244637)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,810,000 (Direct Cost: ¥3,700,000、Indirect Cost: ¥1,110,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 造血幹細胞移植 / 免疫回復 / サイトカイン放出症候群 / 類洞閉塞症候群 / インターロイキン6 / 経直腸門脈シンチグラフィー / WT1 / PT/Cy / 同種造血幹細胞移植 / SOS / ハプロ移植 / 免疫再構築 / 血球貪食症候群 / フェリチン / サイトカイン / 移植 / 臨床

Outline of Final Research Achievements

The pretransplant WT1 mRNA level was a powerful prognostic factor in allo-HCT for non-CR AML patients. High peak serum IL-6 level after HLA-haploidentical allogeneic hematopoietic cell transplantation with post-transplantation cyclophosphamide (PT/Cy-haplo) was identified a significant risk factor for very severe cytokine release syndrome (CRS) and poor 3-year overall survival. Counts of CD4+ T-cell subsets, CD8+ T-cell subsets, and NK cells were lower in PT/Cy-haplo than those in HLA-matched related HCT. The immune recovery pace in PT/Cy-haplo subsequently caught up with that of the other grafts. The regulatory T cells (Tregs) to conventional CD4+ T-cell (Tcon) ratio was significantly higher in PT/Cy-haplo. A higher Tregs-to-Tcon ratio was significantly associated with a lower incidence of chronic GVHD. A diagnostic approach using per-rectal portal scintigraphy for sinusoidal obstruction syndrome was useful.

Academic Significance and Societal Importance of the Research Achievements

WT1が非寛解急性骨髄性白血病に対する同種造血幹細胞移植の有用な予後因子であることを示し、移植適応を考える上で有用となる。移植後大量シクロフォスファミドを用いたHLA半合致移植（PT/Cyハプロ移植）後に発症し、生命を脅かす可能性があるサイトカイン放出症候群の代理マーカーとしてIL-6を見出し、診断および治療法の開発に有用となる。PT/Cyハプロ移植後の免疫回復を明らかにし、CD4 + T細胞/制御性T細胞比が低いことが慢性GVHDが少ない機序である可能性を示した。非侵襲的門脈圧測定法である経直腸門脈シンチグラフィーが診断困難な移植後類洞閉塞症候群の診断法として有用であることを示した。

Research Products

• [Journal Article] Clinical Impacts of Using Serum IL-6 Level as an Indicator of Cytokine Release Syndrome after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide. (2019)
  • Author(s): Nishimoto M, Hirose A, Koh H, Nakamae M, Nanno S, Okamura H, Nakane T, Nakashima Y, Hino M, Nakamae H
  • Journal Title: Biol Blood Marrow Transplant Volume: 25 Issue: 10 Pages: 2061-2069
  • DOI: 10.1016/j.bbmt.2019.06.003
  • Peer Reviewed
• [Journal Article] A prospective observational study of immune reconstitution following transplantation with post-transplant reduced-dose cyclophosphamide from HLA-haploidentical donors (2019)
  • Author(s): Nakamae H, Fujii K, Nanno S, Okamura H, Nakane T, Koh H, Nakashima Y, Nakamae M, Hirose A, Teshima T, Hino M
  • Journal Title: Transpl Int Volume: 32 Issue: 12 Pages: 1322-1332
  • DOI: 10.1111/tri.13494
  • Peer Reviewed
• [Journal Article] Phase I study of graft-versus-host disease prophylaxis including bortezomib for allogeneic hematopoietic cell transplantation from unrelated donors with one or two HLA loci mismatches in Japanese patients (2019)
  • Author(s): Nakane T, Okamura H, Tagaito Y, Koh S, Yoshimura T, Makuuchi Y, Nanno S, Nakamae M, Hirose A, Nakashima Y, Koh H, Hino M, Nakamae H
  • Journal Title: Int J Hematol Volume: 110 Issue: 6 Pages: 736-742
  • DOI: 10.1007/s12185-019-02743-6
  • Peer Reviewed
• [Journal Article] The Proportional Relationship between Pre-transplant WT1 mRNA Levels and Risk of Mortality after Allogeneic Hematopoietic Cell Transplantation in Acute Myeloid Leukemia Not in Remission (2019)
  • Author(s): Ido K, Nakamae M, Koh H, Okamura H, Nanno S, Nishimoto M, Takeoka Y, Hirose A, Nakashima Y, Hashimoto Y, Nakane T, Hino M, Nakamae H
  • Journal Title: Transplantation Volume: - Issue: 10 Pages: 2201-2210
  • DOI: 10.1097/tp.0000000000002662
  • Peer Reviewed
• [Journal Article] A noninvasive diagnostic approach using per-rectal portal scintigraphy for sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation (2019)
  • Author(s): 1.Okamura H, Koh H, Takakuwa T, Ido K, Makuuchi Y, Ine S, Nanno S, Nakashima Y, Nakane T, Jogo A, Yamamoto A, Hamuro M, Yoshida A, Kotani K, Higashiyama S, Kawabe J, Shiomi S, Ohsawa M, Hino M, Nakamae H.
  • Journal Title: Bone Marrow Transplantation Volume: -
  • Peer Reviewed
• [Journal Article] Diagnostic value of serum ferritin and cytokine profiles of hemophagocytic syndrome following allogeneic hematopoietic cell transplantation: methodological issues. (2018)
  • Author(s): Koh H, Nanno S, Hino M, Nakamae H
  • Journal Title: Leukemia Lymphoma. Volume: 59 Issue: 3 Pages: 772-773
  • DOI: 10.1080/10428194.2017.1361033
  • NAID: 120006601147
  • Peer Reviewed
• [Journal Article] Autonomic Nervous System Pretransplant Malfunction is a Powerful Predictor of Survival after Allogeneic Hematopoietic Cell Transplantation. (2017)
  • Author(s): Nakane T, Nakamae M, Koh H, Nishimoto M, Nakashima Y, Hirose A, Hino M, Nakamae H..
  • Journal Title: Transplantation Volume: 101 Issue: 11 Pages: 2801-2809
  • DOI: 10.1097/tp.0000000000001813
  • Peer Reviewed
• [Journal Article] Drug interactions and safety profiles with concomitant use of caspofungin and calcineurin inhibitors in allogeneic hematopoietic cell transplantation. (2017)
  • Author(s): Nishimoto M, Koh H, Tokuwame A, Makuuchi Y, Kuno M, Takakuwa T, Okamura H, Koh S, Yoshimura T, Nanno S, Nakamae M, Hirose A, Nakashima Y, Nakane T, Hino M, Nakamae H.
  • Journal Title: British Journal of Clinical Pharmacology Volume: 83 Issue: 9 Pages: 000-2007
  • DOI: 10.1111/bcp.13303
  • Peer Reviewed
• [Journal Article] Diagnostic usefulness of plasma presepsin (soluble CD14-subtype) for diagnosing hemophagocytic syndrome in hematological malignancies. (2017)
  • Author(s): Koh H, Nanno S, Katayama T, Hirose A, Nakamae M, Hino M, Nakamae H
  • Journal Title: Leukemia Lymphoma. Volume: 58 Issue: 10 Pages: 2489-2492
  • DOI: 10.1080/10428194.2017.1292356
  • NAID: 120006532428
  • Peer Reviewed
• [Journal Article] Diagnostic value of serum ferritin and the risk factors and cytokine profiles of hemophagocytic syndrome following allogeneic hematopoietic cell transplantation (2017)
  • Author(s): Nanno S, Koh H, Nakashima Y, Katayama T, Okamura H, Koh S, Yoshimura T, Nishimoto M, Hayashi Y, Nakamae M, Hirose A, Nakane T, Hino M, Nakamae H
  • Journal Title: Leukemia Lymphoma. Volume: 58 Issue: 7 Pages: 1664-1672
  • DOI: 10.1080/10428194.2016.1262034
  • NAID: 120006532429
  • Peer Reviewed
• [Presentation] Phase I study of bortezomib-added GVHD prophylaxis for allo-HCT from HLA mismatched unrelated donor (2019)
  • Author(s): Takahiko Nakane, Hiroshi Okamura, Yumi Tagaito, Shiro Koh, Yousuke Makuuchi, Satoru Nanno, Takuro Yoshimura, Asao Hirose, Mika Nakamae, Yasuhiro Nakashima, Hideo Koh, Masayuki Hino, Hirohisa Nakamae
  • Organizer: 第81回日本血液学会
• [Presentation] Development of personalized survival prediction curves in allogeneic HCT using machine learning (2019)
  • Author(s): Hiroshi Okamura, Mika Nakamae, Makoto Moriguchi, Yusuke Okayama, Nao Tanizawa, Yumi Tagaito, Tetsuya Hayashi, Kazuki Sakatoku, Kentaro Ido, Naonori Harada, Satoru Nanno, Yasuhiro Nakashima, Hideo Koh, Takahiko Nakane, Asao Hirose, Kohei Yabusaki, Masayuki Hino, Hirohisa Nakamae
  • Organizer: 第81回日本血液学会
• [Presentation] Impact of Donor KIR and HLA Genotypes on Clinical Outcomes According to Pre-Transplant Remission Status after HLA-Haploidentical Transplantation with Post-Transplantation Cyclophosphamide (2019)
  • Author(s): Ido K, Koh H, Okamura H, Koh S, Nanno S, Nishimoto M, Hirose A, Nakamae M, Nakashima Y, Nakane T, Hino M, Nakamae H
  • Organizer: 61th American Society of Hematology annual meeting
  • Int'l Joint Research
• [Presentation] Pretransplant Risk Factors for Calcineurin Inhibitor-Induced Encephalopathy and Limbic Encephalitis Following Allogeneic Hematopoietic Cell Transplantation (2019)
  • Author(s): Tanizawa N, Koh H, Okamura H, Shiro K, Nanno S, Nishimoto M, Hirose A, Nakamae M, Nakashima Y, Nakane T, Hino M, Nakamae H
  • Organizer: 61th American Society of Hematology annual meeting
  • Int'l Joint Research
• [Presentation] 非寛解期AMLの移植前末梢血WT1mRNAレベルに比例し同種造血幹細胞移植後の死亡リスクが増加する (2019)
  • Author(s): 井戸健太郎、中前美佳、康 秀男、岡村浩史、南野 智、西本光孝、橋本由徳、武岡康信、廣瀬朝生、中嶋康博、中根孝彦、日野雅之、中前博久
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] HLA一致血縁又は非血縁ドナーからの同種移植におけるPTCｙ及びTacを用いたGVHD予防-臨床第2相試験中間解析- (2019)
  • Author(s): 中根孝彦、中前博久、南野 智、岡村浩史、西本光孝、幕内陽介、長崎譲慈、田垣内優美、林 哲哉、原田尚憲、井戸健太郎、酒徳一希、谷澤 直、岡山裕介、森口 慎、廣瀬朝生、中前美佳、中嶋康博、康 秀男、武岡康信、日野雅之
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] SOS診断における経直腸門脈シンチグラフィーとシアトル基準の比較検討 (2019)
  • Author(s): 岡村浩史、康 秀男、高桑輝人、井戸健太郎、幕内陽介、井根省二、南野 智、中嶋康博、中根孝彦、城後篤志、山本 晃、羽室雅夫、吉田淳史、小谷晃平、河邊譲治、東山滋明、塩見 進、大澤政彦、日野雅之、中前博久
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] 同種造血幹細胞移植後Stenotrophomonas maltophilia感染症の特徴および発症関連因子の検討 (2019)
  • Author(s): 廣瀬朝生、康 秀男、中前美佳、中根孝彦、中嶋康博、武岡康信、山田康一、掛屋 弘、日野雅之、中前博久
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] 同種造血幹細胞移植前の血清beta-2 microgloburinは全生存率の予後予測マーカーとなり得る (2019)
  • Author(s): 原田尚憲、中根孝彦、中前美佳、田垣内優美、林 哲哉、井戸健太郎、幕内陽介、岡村浩史、南野 智、西本光孝、武岡康信、廣瀬朝生、中嶋康博、康 秀男、日野雅之、中前博久
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] 同種造血細胞移植後難治性ウイルス感染症に対する免疫グロブリン大量療法の有効性・安全性の検討 (2019)
  • Author(s): 井戸健太郎、中根孝彦、岡村浩史、南野 智、西本光孝、廣瀬朝生、中前美佳、中嶋康博、康 秀男、日野雅之、中前博久
  • Organizer: 第42回日本造血細胞移植学会総会
• [Presentation] Noninvasive diagnostic approach by per rectal portal scintigraphy for sinusoidal obstruction syndrome after allogeneic hematopoietic cell transplantation (2018)
  • Author(s): Okamura H, Koh H, Ido K, Makuuchi Y, Takakuwa T, Ine S, Nanno S, Nakashima Y, Nakane T, Jogo A, Yamamoto A, Hamuro M, Yoshida A, Kotani K, Higashiyama S, Kawabe J, Shiomi S, Ohsawa M, Hino M, Nakamae H
  • Organizer: 60th ASH (American Society of Hematology)
  • Int'l Joint Research
• [Presentation] Pre-transplant Serum Beta-2 Microglobulin Level is**a Potential Novel Prognostic Marker for Overall Survival after Allogeneic Hematopoietic Stem Cell Transplantation (2018)
  • Author(s): Harada H, Nakane T, Nakamae M, Okamura H, Nanno S, Nishimoto M, Takeoka Y, Hirose A, Nakashima Y, Koh H, Hino M, Nakamae H
  • Organizer: 60th ASH (American Society of Hematology)
  • Int'l Joint Research
• [Presentation] The Proportional Association between WT1 mRNA level in Peripheral Blood before Allogeneic Hematopoietic Cell Transplantation and Risk of Mortality in Acute Myeloid Leukemia Not in Remission (2018)
  • Author(s): Ido K, Nakamae M, Koh H, Okamura H, Nanno S, Nishimoto M, Hashimoto Y, Takeoka Y, Hirose A, Nakashima Y, Nakane T, Hino M, Nakamae H
  • Organizer: 60th ASH (American Society of Hematology)
  • Int'l Joint Research
• [Presentation] 再生不良性貧血に対するフルダラビン、メルファラン、TBI ４Gy前処置による臍帯血移植 (2018)
  • Author(s): 康 秀男、吉村卓朗、田垣内優美、林 哲哉、原田尚憲、岡村浩史、南野 智、廣瀬朝生、中前美佳、中嶋康博、中根孝彦、日野雅之、中前博久
  • Organizer: 第80回日本血液学会
• [Presentation] 同種造血幹細胞移植後患者のIgGサブクラスと慢性期感染症の関連性の解析 (2018)
  • Author(s): 康 史朗、西本光孝、武岡康信、中嶋康博、康 秀男、中根孝彦、廣瀬朝生、中前美佳、日野雅之、中前博久
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] Pre-Transplant Transferrin Saturation Levels As a Predictive Marker for Invasive Fungal Disease Following Allogeneic Hematopoietic Stem Cell Transplantation (2017)
  • Author(s): Nanno S, Koh H, Nishimoto M, Nakane T, Nakashima Y, Takeoka Y, Nakamae M, Hirose A, Hino M, Nakamae H
  • Organizer: 59th American Society of Hematology
  • Int'l Joint Research
• [Presentation] Post-Transplant Cyclophosphamide Contributes to Impaired Graft-Versus-Leukemia Effects and Regulates Graft-Versus-Host Disease in the Murine Stem Cell Transplant Model (2017)
  • Author(s): Makuuchi Y, Nakashima Y, Koh H, Nakane T, Nakamae H, Hino M
  • Organizer: 59th American Society of Hematology
  • Int'l Joint Research
• [Presentation] 同種移植後の深在性真菌症の発症予測マーカーとしてのトランスフェリン飽和 (2017)
  • Author(s): 南野 智、康 秀男、西本光孝、中根孝彦、中嶋康博、武岡康信、中前美佳、廣瀬朝生、日野雅之、中前博久
  • Organizer: 第40回日本造血細胞移植学会総会
• [Presentation] 移植後大量シクロフォスファミドは同種移植のマウスモデルにおいてGVHDを抑制し、GVL効果を減弱させる (2017)
  • Author(s): 幕内陽介、中嶋康博、康 秀男、中根孝彦、日野雅之、中前博久
  • Organizer: 第40回日本造血細胞移植学会総会
• [Remarks] 血液腫瘍制御学HPの項目「業績」
  • URL: http://www.med.osaka-cu.ac.jp/labmed/
• [Remarks] 大阪市立大学・大学院医学研究科 血液腫瘍制御学
  • URL: http://www.med.osaka-cu.ac.jp/labmed/