Innate immune signals in allogeneic hematopoietic stem cell transplantation

• Project/Area Number: 25860775
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Hematology
• Research Institution: Hokkaido University
• Principal Investigator: SHIRATORI Souichi 北海道大学, 医学(系)研究科(研究院), 客員研究員 (00645905)
• Project Period (FY): 2013-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥4,030,000 (Direct Cost: ¥3,100,000、Indirect Cost: ¥930,000); Fiscal Year 2014: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2013: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 造血幹細胞移植 / 移植片対宿主病 / GVHD / 移植片対白血病効果 / Toll Like Receptor / MyD88 / 白血病 / T細胞 / 免疫 / 腫瘍 / TLRシグナル / TLRノックアウトＴ細胞

Outline of Final Research Achievements

Among several innate immune signaling molecules, MyD88 in donor T cells were critical for the maximization of graft versus host disease (GVHD) after murine allogeneic bone marrow transplantation. T cells lack of single upstream molecules of MyD88 caused equivalent GVHD compared to wild type T cells, indicating that an overall blockade of MyD88-dependent signals in T cells are required for GVHD amelioration. MyD88 deficient T cells showed severely impaired Th1 response compared to wild type T cells upon CD3/CD28 stimulation and allogeneic stimulation. MyD88 deficient donor T cells exerted significant graft versus leukemia effects, suggesting that MyD88 inhibitor is a promising therapeutic reagent against GVHD in clinical transplantation.

Research Products

• [Journal Article] Ultra-high level of serum soluble interleukin-2 receptor at diagnosis predicts poor outcome for angioimmunoblastic T-cell lymphoma. (2015)
  • Author(s): Shiratori S, Kosugi-Kanaya M, Shigematsu A, Kobayashi H, Yamamoto S, Kobayashi N, Iwasaki H, Mori A, Kunieda Y, Yutaka T, Kurosawa M, Kakinoki Y, Endo T, Kondo T, Hashino S, Teshima T
  • Journal Title: Leukemia & Lymphoma Volume: - Issue: 9 Pages: 2592-2597
  • DOI: 10.3109/10428194.2014.1001985
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Sustained CD4 and CD8 lymphopenia after rituximab maintenance therapy following bendamustine and rituximab combination therapy for lymphoma (2015)
  • Author(s): Tsutsumi Y, Ito S, Ohigashi H, Miyashita N, Shimono J, Shiratori S, Teshima T
  • Journal Title: Leukemia & Lymphoma Volume: 11 Pages: 1-9
  • Peer Reviewed
• [Journal Article] Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome. (2014)
  • Author(s): Shiratori S, Fujimoto K, Nishimura M, Hatanaka KC, Kosugi-Kanaya M, Okada K, Sugita J, Shigematsu A, Hashimoto D, Endo T, Kondo T, Abe R, Hashino S, Matsuno Y, Shimizu H, Teshima T.
  • Journal Title: Hematol Oncol Volume: Epub Ahead of Print Issue: 1 Pages: 9-16
  • DOI: 10.1002/hon.2162
  • NAID: 120005981361
  • Peer Reviewed / Open Access
• [Journal Article] Analysis of the influence of dabigatran on coagulation factors and inhibitors. (2014)
  • Author(s): Tsutsumi Y, Shimono J, Ohhigashi H, Ito S, Shiratori S, Teshima T
  • Journal Title: International Journal of Laboratory Hematology Volume: 37 Issue: 2 Pages: 225-230
  • DOI: 10.1111/ijlh.12270
  • Peer Reviewed
• [Journal Article] Bone Marrow Graft-versus-Host Disease: Evaluation of Its Clinical Impact on Disrupted Hematopoiesis after Allogeneic Hematopoietic Stem Cell Transplantation (2014)
  • Author(s): Souichi Shiratori, Mizuha Kosugi-Kanaya, Satoshi Ueha, Junichi Sugita1, Akio Shigematsu, Takeshi Kondo, Daigo Hashimoto, Katsuya Fujimoto, Tomoyuki Endo, Mitsufumi Nishio, Satoshi Hashino, Yoshihiro Matsuno, Kouji Matsushima, Junji Tanaka, Masahiro Imamura, Takanori Teshima
  • Journal Title: Biol Blood Marrow Transplant Volume: 20 Issue: 4 Pages: 495-500
  • DOI: 10.1016/j.bbmt.2013.12.568
  • NAID: 120005427744
  • Peer Reviewed / Open Access
• [Journal Article] Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single-center experience (2014)
  • Author(s): Shiratori S, Wakasa K, Okada K, Sugita J, Akizawa K, Shigematsu A, Hashimoto D, Fujimoto K, Endo T, Kondo T, Shimizu C, Hashino S, Teshima T
  • Journal Title: Clin Transplant Volume: 28(6) Issue: 6 Pages: 656-661
  • DOI: 10.1111/ctr.12356
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Successful engraftment in HLA-mismatched bone marrow transplantation despite the persistence of high-level donor-specific anti-HLA-DR antibody. (2013)
  • Author(s): Shiratori S, Ito M, Yoneoka M, Hayasaka K, Hayase E, Iwasaki J, Sugita J, Shigematsu A, Fujimoto K, Kondo T, Shimizu C, Teshima T.
  • Journal Title: Transplantation Volume: 96(5) Issue: 5 Pages: e34-e44
  • DOI: 10.1097/tp.0b013e31829f7595
  • Peer Reviewed
• [Presentation] タクロリムス徐放製剤を用いたGVHD予防法による造血幹細胞移植の成績 (2015)
  • Author(s): 大東寛幸、伊東慎市、白鳥聡一、堤豊
  • Organizer: 第37回日本造血細胞移植学会総会
  • Place of Presentation: 神戸国際会議場（兵庫県・神戸市）
  • Year and Date: 2015-03-05 – 2015-03-07
• [Presentation] A retrospective analysis of AITL in Hokkaido: Clinical impact of sIL-2R as a prognostic factor (2014)
  • Author(s): 白鳥聡一、小杉瑞葉、重松明男、小林一、山本聡、小林直樹、岩崎博、盛暁生、國枝保幸、堤豊、黒澤光俊、柿木康孝、岡田耕平、杉田純一、小野澤真弘、橋本大吾、藤本勝也、遠藤知之、西尾充史、近藤健、橋野聡、豊嶋崇徳
  • Organizer: 第76回日本血液学会学術集会
  • Place of Presentation: 大阪国際会議場（大阪府・大阪市）
  • Year and Date: 2014-10-31 – 2014-11-02
• [Presentation] 菌状息肉症に対する同種造血幹細胞移植の後方視的解析－更なる移植成績の向上に向けて－ (2014)
  • Author(s): 白鳥聡一、山川知宏、江端浩、小笠原励起、佐賀智之、高橋正二郎、岩崎純子、岡田耕平、井端淳、杉田純一、高畑むつみ、重松明男、橋本大吾、藤本勝也、遠藤知之、近藤健、豊嶋崇徳
  • Organizer: 第36回日本造血細胞移植学会総会
  • Place of Presentation: 沖縄コンベンションセンター（宜野湾市）
• [Presentation] Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation ― Risk factors and Therapeutic strategies ― (2013)
  • Author(s): Shiratori S, Akizawa K, Hayase E, Iwasaki J, Okada K, Yasumoto A, Ibata M, Sugita J, Shigematsu A, Fujimoto K, Endo T, Kondo T, Hashino S, Tanaka J, Teshima T.
  • Organizer: 第18回欧州血液学会議
  • Place of Presentation: Stockholmsmassan（Stockholm, Sweden）
• [Presentation] TPO受容体作動薬エルトロンボパグにより生じた骨髄線維症の病態 －ITP症例における解析－ (2013)
  • Author(s): 白鳥 聡一、近藤 健、畑中 佳奈子、早瀬 英子、岩崎 純子、杉田 純一、藤本 勝也、松野 吉宏、豊嶋 崇徳
  • Organizer: 第75回日本血液学会学術集会
  • Place of Presentation: ロイトン札幌（札幌市）
• [Remarks] 北海道大学大学院 医学研究科医学専攻 内科学講座 血液内科学分野
  • URL: http://www.hokudai-hematology.jp/medical/results/