Development of novel thymus-directed strategy for central immune tolerance induction in hemophilia A

• Project/Area Number: 24591430
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Hematology
• Research Institution: Jichi Medical University
• Principal Investigator: MADOIWA Seiji 自治医科大学, 医学部, 講師 (70296119)
• Co-Investigator(Kenkyū-buntansha): KOBAYASHI Eiji 自治医科大学, 医学部, 客員教授 (00245044) ; OHMORI Tsukasa 自治医科大学, 医学部, 講師 (70382843)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2013: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2012: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 血友病 / インヒビター / 免疫寛容 / 人工多能性幹細胞 / 遺伝子治療 / 細胞移植療法 / 胸腺上皮細胞 / 細胞療法

Outline of Final Research Achievements

Hemophilia A is an X-linked, recessive hereditary bleeding disorder due to deficient coagulation factor VIII (FVIII). However, about 30% of patients with severe deficiency develop inhibitors or circulating alloantibodies against infused factor VIII. Once an inhibitor develops, treatment of bleeding episodes is quite difficult due to partial or complete lack of efficacy of replacement therapy. Immune tolerance induction (ITI) by prolonged administration of FVIII concentrates is currently the only therapy proven to eliminate persistent inhibitors in severe hemophilia A. In this project, we investigated central ITI by thymic implantation of epithelial progenitor cells derived from induced pluripotent stem (iPS) cells, which will be isolated from fibroblasts of congenic hemophilia A mice and transduced with the SIV encoding FVIII.

Research Products

• [Journal Article] Endothelial cells and fibrinolysis in sepsis-induced DIC (2015)
  • Author(s): Madoiwa, S.
  • Journal Title: J Intensive Care Volume: 3 Issue: 1 Pages: 1-8
  • DOI: 10.1186/s40560-015-0075-6
  • Peer Reviewed / Open Access
• [Journal Article] Changes in blood coagulation-fibrinolysis markers by pneumatic tourniquet during total knee joint arthroplasty with venous thromboembolism. (2014)
  • Author(s): Watanabe, H., I. Kikkawa, S. Madoiwa, H. Sekiya, S. Hayasaka, and Y. Sakata.
  • Journal Title: J Arthroplasty Volume: 29 Issue: 3 Pages: 569-573
  • DOI: 10.1016/j.arth.2013.08.011
  • Peer Reviewed
• [Journal Article] Addition of recommendations for the use of recombinant human thrombomodulin to the "Expert consensus for the treatment of disseminated intravascular coagulation in Japan" (2014)
  • Author(s): Wada, H., D. I. C. s. Japanese Society of Thrombosis Hemostasis, K. Okamoto, T. Iba, S. Kushimoto, K. Kawasugi, S. Gando, S. Madoiwa, T. Uchiyama, T. Mayumi, and Y. Seki.
  • Journal Title: Thromb Res Volume: 2014 Issue: 4 Pages: 924-925
  • DOI: 10.1016/j.thromres.2014.07.033
  • Peer Reviewed
• [Journal Article] Living donor liver transplantation from an asymptomatic donor with mild coagulation factor IX deficiency: report of a case. (2014)
  • Author(s): Sanada, Y., H. Sasanuma, Y. Sakuma, K. Morishima, N. Kasahara, Y. Kaneda, A. Miki, T. Fujiwara, A. Shimizu, M. Hyodo, Y. Hirata, N. Yamada, N. Okada, Y. Ihara, T. Urahashi, S. Madoiwa, J. Mimuro, K. Mizuta, and Y. Yasuda.
  • Journal Title: Pediatr Transplant Volume: 18 Issue: 8
  • DOI: 10.1111/petr.12358
  • Peer Reviewed / Open Access
• [Journal Article] Paxillin is an intrinsic negative regulator of platelet activation in mice. (2014)
  • Author(s): Sakata, A., T. Ohmori, S. Nishimura, H. Suzuki, S. Madoiwa, J. Mimuro, K. Kario, and Y. Sakata.
  • Journal Title: Thromb J Volume: 12 Issue: 1 Pages: 1-1
  • DOI: 10.1186/1477-9560-12-1
  • Peer Reviewed / Open Access
• [Journal Article] The prevalence of neutralizing antibodies against adeno-associated virus capsids is reduced in young Japanese individuals. (2014)
  • Author(s): Mimuro J, Mizukami H, Shima M, Matsushita T, Taki M, Muto S, Higasa S, Sakai M, Ohmori T, Madoiwa S, Ozawa K, and Sakata Y.
  • Journal Title: J. Med. Virol. Volume: 86 Issue: 11 Pages: 1990-1997
  • DOI: 10.1002/jmv.23818
  • Peer Reviewed / Open Access
• [Journal Article] Combination of thrombin-antithrombin complex, plasminogen activator inhibitor-1, and protein C activity for early identification of severe coagulopathy in initial phase of sepsis: a prospective observational study. (2014)
  • Author(s): Koyama, K., S. Madoiwa, S. Nunomiya, T. Koinuma, M. Wada, A. Sakata, T. Ohmori, J. Mimuro, and Y. Sakata.
  • Journal Title: Crit Care Volume: 18 Issue: 1
  • DOI: 10.1186/cc13190
  • Peer Reviewed
• [Journal Article] Production of functional coagulation factor VIII from iPSCs using a lentiviral vector (2014)
  • Author(s): Kashiwakura Y, Ohmori T, Mimuro J, Madoiwa S, Inoue M, Hasegawa M, Ozawa K, and Sakata Y.
  • Journal Title: Haemophilia Volume: 20 Issue: 1
  • DOI: 10.1111/hae.12311
  • Peer Reviewed
• [Journal Article] Overexpression of factor VII ameliorates bleeding diathesis of factor VIII-deficient mice with inhibitors. (2013)
  • Author(s): Yasumoto A, Madoiwa S, Kashiwakura Y, Ishiwata A, Ohmori T, Mizukami H. Ozawa K, Sakata Y, and Mimuro J.
  • Journal Title: Thromb. Res. Volume: 131 Issue: 5 Pages: 444-449
  • DOI: 10.1016/j.thromres.2013.03.007
  • Peer Reviewed
• [Journal Article] Acquired hemophilia a caused by factor viii inhibitors: Report of a case. (2013)
  • Author(s): Hosoya Y, Matsumura M, Madoiwa S, Zuiki T, Matsumoto S, Nunomiya S, Lefor A, Sata N, Yasuda Y.
  • Journal Title: Surgery today Volume: 43 Issue: 6 Pages: 670-674
  • DOI: 10.1007/s00595-012-0290-x
  • NAID: 10031176090
  • Peer Reviewed
• [Journal Article] Acquired factor v inhibitor associated with life-threatening bleeding and a mixing test result that indicated coagulation factor deficiency. (2013)
  • Author(s): Ashizawa M, Kimura S, Wada H, Sakamoto K, Sato M, Terasako K, Kikuchi M, Nakasone H, Okuda S, Kako S, Yamazaki R, Oshima K, Matsuura K, Ohmori T, Madoiwa S, Nishida J, Mimuro J, Tabei K, Sakata Y, Kanda Y.
  • Journal Title: Hematology Volume: 18 Issue: 5 Pages: 300-304
  • DOI: 10.1179/1607845412y.0000000072
  • Peer Reviewed
• [Journal Article] 分娩後後天性血友病の2例. (2013)
  • Author(s): 野城聡志, 翁家国, 岡塚貴世志, 藤原慎一郎, 大嶺謙, 鈴木隆浩, 森政樹, 永井正, 室井一男, 小澤敬也, 窓岩清治.
  • Journal Title: 臨床血液 Volume: 54 Pages: 2100-2100
  • Peer Reviewed
• [Journal Article] 血友病aクローンブタ (2013)
  • Author(s): 柏倉裕志, 三室淳, 大西彰, 岩元正樹, 窓岩清治, 淵本大一郎, 鈴木俊一, 鈴木美佐枝, 千本昭一郎, 石渡彰, 安本篤史, 坂田飛鳥, 大森司, 橋本径子, 矢崎智子, 坂田洋一
  • Journal Title: 日本血栓止血学会誌 Volume: 24 Pages: 224-224
• [Journal Article] インヒビター保有先天性血友病患者に対する止血治療ガイドライン 2013年改訂版 (2013)
  • Author(s): 酒井 道生(産業医科大学 小児科), 瀧 正志, 家子 正裕, 井田 孔明, 大平 勝美, 勝沼 俊雄, 高橋 芳右, 野上 恵嗣, 日笠 聡, 福武 勝幸, 松下 功, 松本 雅則, 窓岩 清治, 天野 景裕, 岡 敏明, 荻原 建一, 澤田 暁宏, 嶋 緑倫, 白幡 聡, 鈴木 隆史, 竹谷 英之, 花房 秀次, 堀越 泰雄, 松下 正, 松本 剛史, 三室 淳, 吉岡 章
  • Journal Title: 日本血栓止血学会誌 Volume: 24 Pages: 640-658
• [Journal Article] Evaluation of hemostatic biomarker abnormalities that precede platelet count decline in critically ill patients with sepsis (2013)
  • Author(s): Koyama, K., Madoiwa, S., Tanaka, S., Koinuma, T., Wada, M., Sakata, A., Ohmori, T., Mimuro, J., Nunomiya, S. and Sakata, Y.
  • Journal Title: J Crit Care Volume: in press Issue: 5 Pages: 556-563
  • DOI: 10.1016/j.jcrc.2012.10.069
  • Peer Reviewed
• [Journal Article] Minimizing the inhibitory effect of neutralizing antibody for efficient gene expression in the liver with adeno-associated virus 8 vectors. (2013)
  • Author(s): Mimuro J, Mizukami H, Hishikawa S, Ikemoto T, Ishiwata A, Sakata A, Ohmori T, Madoiwa S, Ono F, Ozawa K, and Sakata Y
  • Journal Title: Mol Ther Volume: 21 Issue: 2 Pages: 318-323
  • DOI: 10.1038/mt.2012.258
  • Peer Reviewed
• [Journal Article] Tissue plasminogen activator (tPA) deficiency promotes early phase regeneration in the olfactory epithelium after bulbectomy (2013)
  • Author(s): Makino N, Madoiwa S, Ohmori T, Katoh K, Ookawara S, Kanazawa T, Matsuo O, Ichikawa M, Mimuro J, Ichimura K, Sakata Y
  • Journal Title: International Forum of Allergy & Rhinology Volume: 3 Issue: 6 Pages: 458-467
  • DOI: 10.1002/alr.21124
  • Peer Reviewed
• [Journal Article] Porcine model of hemophilia a. PLoS One. (2012)
  • Author(s): Kashiwakura Y
  • Journal Title: PLoS One. Volume: 7(11) Issue: 11 Pages: e49450-e49450
  • DOI: 10.1371/journal.pone.0049450
  • Peer Reviewed
• [Journal Article] Morphological assessment of the luminal surface of olfactory epithelium in mice deficient in tissue plasminogen activator following bulbectomy. (2012)
  • Author(s): Makino, N
  • Journal Title: The Journal of Laryngology ＆ Otology. Volume: 126(11) Issue: 11 Pages: 1114-1120
  • DOI: 10.1017/s002221511200206x
  • Peer Reviewed
• [Journal Article] Intra-articular injection of mesenchymal stem cells expressing coagulation factorameliorates hemophilic arthropathy in factor VIII-deficient mice. (2012)
  • Author(s): Kashiwakura, Y
  • Journal Title: J Thromb Haemost. Volume: 10(9) Issue: 9 Pages: 1802-1813
  • DOI: 10.1111/j.1538-7836.2012.04851.x
  • Peer Reviewed
• [Journal Article] Il2rg gene-targeted severe combined immunodeficiency pigs (2012)
  • Author(s): Suzuki S, Iwamoto M, Saito Y, Fuchimoto D, Sembon S, Suzuki M, Mikawa S, Hashimoto M, Aoki Y, Najima Y, Takagi S, Suzuki N, Suzuki E, Kubo M, Mimuro J, Kashiwakura Y, Madoiwa S, et al.
  • Journal Title: Cell Stem Cell Volume: 10 Issue: 6 Pages: 753-758
  • DOI: 10.1016/j.stem.2012.04.021
  • Peer Reviewed
• [Journal Article] FTY720 improves functional recovery after spinal cord injury by primarily nonimmunomodulatory mechanisms (2012)
  • Author(s): Norimatsu Y, Ohmori T, Kimura A, Madoiwa S, Mimuro J, Seichi A, Yatomi Y, Hoshino Y, Sakata Y.
  • Journal Title: Am J Pathol Volume: 180(4) Issue: 4 Pages: 1625-35
  • DOI: 10.1016/j.ajpath.2011.12.012
  • Peer Reviewed
• [Journal Article] Lack of association between serum paraoxonase-1 activity and residual platelet aggregation during dual anti-platelet therapy (2012)
  • Author(s): Ohmori, T., et al.
  • Journal Title: Thromb Res Volume: 129 Issue: 4 Pages: e36-e40
  • DOI: 10.1016/j.thromres.2011.10.033
  • Peer Reviewed
• [Journal Article] Immune response against serial infusion of factor VIII antigen through an implantable venous-access device system in haemophilia A mice (2012)
  • Author(s): Madoiwa, S., et al.
  • Journal Title: Haemophilia Volume: 18 Issue: 3
  • DOI: 10.1111/j.1365-2516.2011.02686.x
  • Peer Reviewed
• [Presentation] Progression of thrombosis and hemostasis 血友病におけるインヒビター発生機序とその制御手法 (2013)
  • Author(s): 窓岩清治
  • Organizer: 日本血栓止血学会学術集会
  • Place of Presentation: 札幌
• [Presentation] Regulation of plasminogen activator inhibitor -1 promotes immune tolerance to factor VIII in murine hemophilia A. (2013)
  • Author(s): Seiji Madoiwa, Tsukasa Ohmori, Toshio Miyata, Takashi Dan, Yuji Kashiwakura, Asuka Sakata, Jun Mimuro, Kiyotaka Okada, Shigeru Ueshima, Hitoshi Endo, Makoto Inoue, Mamoru Hasegawa, Osamu Matsuo, Keiya Ozawa, Yoichi Sakata
  • Organizer: 2013 Congress of Internationl Society on Thrombosis and Haemostasis
  • Place of Presentation: Amsterdam, Netherland
• [Presentation] REGULATION OF PLASMINOGEN ACTIVATOR INHIBITOR-1 REDUCES IMMUNE RESPONSE TO FACTOR VIII IN MURINE HEMOPHILIA A. (2013)
  • Author(s): Seiji Madoiwa, Tsukasa Ohmori, Toshio Miyata, Takashi Dan, Yuji Kashiwakura, Asuka Sakata, Jun Mimuro, Kiyotaka Okada, Shigeru Ueshima, Hitoshi Endo, Makoto Inoue, Mamoru Hasegawa, Osamu Matsuo, Keiya Ozawa, Yoichi Sakata
  • Organizer: 2013 East Asia Hemophilia Forum
  • Place of Presentation: Seoul, South Korea
  • Invited
• [Presentation] Regulation of plasminogen activator inhibitor-1 promotes immune tolerance to factor VIII in murine hemophilia A (2013)
  • Author(s): Madoiwa S, Ohmori T, Kashiwakura Y, Sakata A, Mimuro J, Sakata Y
  • Organizer: the XXIV Congress of the ISTH
  • Place of Presentation: Amsterdam, Netherland