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Induction of Immune Tolerance by Neonatal Intravenous Injection of Human Factor VIII in Murine Hemophilia A

Research Project

Project/Area Number 15591021
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionJICFII MEDICAL SCHOOL

Principal Investigator

MADOIWA Seiji  Jichi Medical School, Department of Medicine, Assistant Professor, 医学部, 講師 (70296119)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Fiji  Jichi Medical School, Department of Medicine, Professor, 医学部, 教授 (00245044)
SAKATA Yoichi  Jichi Medical School, Department of Medicine, Professor, 医学部, 教授 (40129028)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2003: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsFactor VIII / Hemophilia A / Immune tolerance / Neonate / knockout mice / ウイルスベクター
Research Abstract

Inhibitory antibody formation is the most serious complication of factor VIII replacement therapy in patients with hemophilia A. Factor VIII-deficient mice served as a model of severe hemophilia A to characterize the immune response to human factor VIII and to study new approaches for induction of immune tolerance. Neither anti-factor VIII inhibitory antibodies nor anti-factor VIII IgGs were observed in 13 of 14 adult mice that received 0.05 unit/g body weight of human factor VIII intravenously within 24 hours after birth, as well as repeated injections as adults. In contrast, high factor VIII antibody titers (>50 Bethesda units/mL) were found in 7 of 13 mice injected on day 3 post-partum and in all adult mice that had not been treated neonatally. One out of 9 mice and 3 of 17 mice developed high-titer anti-factor VIII inhibitory antibody, when they were initially treated with 2-fold (0.1 unit/g body weight) and 10-fold higher doses (0.5 unit/g body weight) factor VIII on day 0 respectively. A human factor VIII specific T cell proliferative response was absent in splenocytes obtained from neonatally treated mice. However, the tolerant mice immunized with tetanus toxoid developed high anti-tetanus toxoid antibody, demonstrating that tolerance is factor VIII specific. The splenocytes failed to proliferate or produce interferon-γ in response to factor VIII stimulation, yet still secreted significant amounts of interleukin-2 and were restored proliferation by the addition of exogenous interferon-γ or the interleukin-12, suggesting that the lack of inhibitor to factor VIII is due to interferon-γ dependent anergy. These studies indicate that exposure on day 0 to physiological levels of factor VIII antigen might be important for induction of immune tolerance. This immune tolerance model may provide a basis for new approaches regarding prevention of factor VIII inhibitors during replacement therapy.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (42 results)

All 2005 2004 2003 Other

All Journal Article (30 results) Book (1 results) Publications (11 results)

  • [Journal Article] Protection of plasminogen inhibitor-1 deficient mice from nasal allergy.2005

    • Author(s)
      Sejima T
    • Journal Title

      J Immunol (in press)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Gene silencing in rat-liver and limb grafts by rapid injection of small interference RNA.2005

    • Author(s)
      Sato Y
    • Journal Title

      Transplantation 79

      Pages: 240-243

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] KRP-203,a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.2005

    • Author(s)
      Shimizu H
    • Journal Title

      Circulation 111

      Pages: 222-229

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] KRP-203, a novel synthetic immunosuppressant, prolongs graft survival and attenuates chronic rejection in rat skin and heart allografts.2005

    • Author(s)
      Shimizu H
    • Journal Title

      Circulation 111

      Pages: 222-229

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A.2004

    • Author(s)
      Madoiwa S
    • Journal Title

      J Thromb Haemost 2

      Pages: 754-762

    • NAID

      10020605038

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Effect of ureteral obstruction on matrix metalloproteinase-2 in rat renal cortex.2004

    • Author(s)
      Iimura O
    • Journal Title

      Clin Exp Nephrol 8

      Pages: 223-229

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sustained transgene expression by human cord blood derived CD34(+) cells transduced with simian immunodeficiency virus agmTYO1-based vector carrying the human coagulation factor VIII gene in NOD/SCID mice.2004

    • Author(s)
      Kikuchi J
    • Journal Title

      J Gene Med 6

      Pages: 1049-1060

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression profiles of fibrinolytic components in nasal mucosa.2004

    • Author(s)
      Sejima T
    • Journal Title

      Histochem Cell Biol 122

      Pages: 61-73

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of gamma Ala327Thr : formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism.2004

    • Author(s)
      Hamano A
    • Journal Title

      Blood 103

      Pages: 3045-3050

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Specific detection of human coagulation factor IX in cynomolgus macaques.2004

    • Author(s)
      Mimuro J
    • Journal Title

      J Thromb Haemost 2

      Pages: 275-280

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Expression of human coagulation factor VIII in adipocytes transduced with the simian immunodeficiency virus agmTYO1-based vector for hemophilia A gene therapy.2004

    • Author(s)
      Ogata K
    • Journal Title

      Gene Ther 11

      Pages: 253-259

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Establishment of Cre/LoxP recombination system in transgenic rats.2004

    • Author(s)
      Sato Y
    • Journal Title

      Biochem Biophys Res Commun 319

      Pages: 1197-1202

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Sustained transgene expression by human cord blood derived CD34(+) cells transduced with simian immunodeficiency virus agmTYO1-based vectors carrying the human coagulation factor VIII gene in NOD/SCID mice.2004

    • Author(s)
      Kikuchi J
    • Journal Title

      J Gene Med 6

      Pages: 1049-1060

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of gammaAla327Thr : formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism.2004

    • Author(s)
      Hamano A
    • Journal Title

      Blood 103

      Pages: 3045-3050

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Establishment of Cre/LoxP recombination system in transgenic rats.2004

    • Author(s)
      Sato Y
    • Journal Title

      Biochem Biophys Res Commun. 319

      Pages: 1197-1202

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A.2004

    • Author(s)
      Madoiwa S
    • Journal Title

      J Thromb Haemost. 2

      Pages: 754-762

    • NAID

      10020605038

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Fibrinogen and fibrin degradation products by leukocyte elastase.2004

    • Author(s)
      Madoiwa S
    • Journal Title

      Nippon Rinsho. 62 Suppl 12

      Pages: 611-614

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Effect of ureteral obstruction on matrix metalloproteinase-2 in rat renal cortex.2004

    • Author(s)
      Iimura O
    • Journal Title

      Clin Exp Nephrol. 8

      Pages: 223-229

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Sustained transgene expression by human cord blood derived CD^+_<34> cells transduced with simian immunodeficiency virus agmTYO1-based vectors carrying the human coagulation factor VIII gene in NOD/SCID mice.2004

    • Author(s)
      Kikuchi J
    • Journal Title

      J Gene Med. 6(10)

      Pages: 1049-1060

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression profiles of fibrinolytic components in nasal mucosa.2004

    • Author(s)
      Sejima T
    • Journal Title

      Histochem Cell Biol. 122(1)

      Pages: 61-73

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γAla327 Thr : formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism.2004

    • Author(s)
      Hamano A
    • Journal Title

      Blood. 103(8)

      Pages: 3045-3050

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Specific detection of human coagulation factor IX in cynomolgus macaques.2004

    • Author(s)
      Mimuro J
    • Journal Title

      J Thromb Haemost. 2

      Pages: 275-280

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Expression of human coagulation factor VIII in adipocytes transduced with the simian immunodeficiency virus agmTYO1-based vector for hemophilia A gene therapy.2004

    • Author(s)
      Ogata K
    • Journal Title

      Gene Ther. 11

      Pages: 253-259

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hypofibrinogenemia caused by a nonsense mutation in the fibrinogen Bbeta chain gene.2003

    • Author(s)
      Mimuro J
    • Journal Title

      J Thromb Haemost 1

      Pages: 2356-2359

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] In vitro platelet activation by an echo contrast agent.2003

    • Author(s)
      Shigeta K
    • Journal Title

      J Ultrasound Med 22

      Pages: 365-373

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Modified Bentall operation in a patient with hemophilia A.2003

    • Author(s)
      Kaminishi Y
    • Journal Title

      Jpn J Thorac Cardiovasc Surg 51

      Pages: 68-70

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Defective sorting to secretory vesicles in trans-Golgi network is partly responsible for protein C deficiency : molecular mechanisms of impaired secretion of abnormal protein C R169W, R352W, and G376D.2003

    • Author(s)
      Naito M
    • Journal Title

      Circ Res 92

      Pages: 865-872

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] DNA immunization of the grafted liver by particle-mediated gene gun.2003

    • Author(s)
      Nakamura M
    • Journal Title

      Transplantation 76

      Pages: 1369-1375

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hypofibrinogenemia caused by a nonsense mutation in the fibrinogen Bbeta chain gene.2003

    • Author(s)
      Mimuro J
    • Journal Title

      Thromb Haemost 1

      Pages: 2356-2359

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Defective sorting to secretory vesicles in trans-Golgi network is partly responsible for protein C deficiency : molecular mechanisms of impaired secretion of abnormal protein C R169W,R352W, and G376D.2003

    • Author(s)
      Naito M
    • Journal Title

      Circ Res 92

      Pages: 865-872

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Book] 周産期の出血と血栓症2004

    • Author(s)
      窓岩 清治
    • Total Pages
      476
    • Publisher
      金原出版
    • Related Report
      2004 Annual Research Report
  • [Publications] Madoiwa S: "Induction of immune tolerance by neonatal intravenous injection of human factor VIII in murine hemophilia A."J.Thromb.Haemost.2004 May issue. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Hamano A: "Thrombophilic dysfibrinogen Tokyo V with the amino acid substitution of γAla-327 to Thr : Formation of fragile but fibrinolysis-resistant fibrin clots and its relevance to arterial thromboembolism."Blood. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Kikuchi J: "Sustained transgene expression by human cord blood-derived CD34+ cells transduced with simian immunodeficiency virus agmTYO1-based vectors carrying the human coagulation factor VIII gene in NOD/SCID mice."J.Gene Med.. (in press).

    • Related Report
      2003 Annual Research Report
  • [Publications] Mimuro J: "Specific detection of human coagulation factor IX in cynomolgus macaques."J.Thromb.Haemost.. 2. 275-280 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ogata K: "Expression of human coagulation factor VIII in adipocytes transduced with the simian immunodeficiency virus agmTYO1-based vector for hemophilia A gene therapy."Gene Ther.. 11. 253-259 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Mimuro J: "Hypofibrinogenemia caused by a nonsense mutation in the fibrinogen B β chain gene."J.Thromb.Haemost.. 1(11). 2356-2359 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Sigeta K: "In vitro platelet activation by an echo-contrast agent."J Ultrasound Med.. 22. 365-373 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Naito M: "Defective sorting to secretory vesicles in the trans Golgi network is partly responsible for protein C deficiency : Molecular mechanism of impaired secretion of abnormal protein C R169W, R352W and G376D."Circ.Res.. 92. 865-872 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kaminishi Y: "Modified Bentall operation in a patient with hemophilia A."J.J.Thor Cardiovasc Surg. 51(2). 68-70 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 窓岩清治: "DIC:癌の凝固線溶系への挑戦"日本検査血液学会雑誌. 4(5). 44-51 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 窓岩清治: "DICの診断-線溶系マーカー(Novel molecular markers of fibrinolysis)"医学のあゆみ. 206. 81-85 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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