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Induction of factor VIII specific unresponsiveness by intrathymic factor VIII injection in murine hemophilia A

Research Project

Project/Area Number 17591006
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionJichi Medical University

Principal Investigator

MADOIWA Seiji  Jichi Medical University, Center for Molecular Medicine, Division of Cell and Molecular Medicine, 医学部, 講師 (70296119)

Co-Investigator(Kenkyū-buntansha) KOBAYASHI Eiji  Jichi Medical University, Center for Molecular Medicine, Division of Cell and Molecular Medicine, 医学部, 教授 (00245044)
SAKATA Yoichi  Jichi Medical University, Center for Molecular Medicine, Division of Cell and Molecular Medicine, 医学部, 教授 (40129028)
Project Period (FY) 2005 – 2006
Project Status Completed (Fiscal Year 2006)
Budget Amount *help
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,600,000 (Direct Cost: ¥1,600,000)
Fiscal Year 2005: ¥1,900,000 (Direct Cost: ¥1,900,000)
Keywordshemophilia A / factor VIII / inhibitor / immune tolerance / thymus / regulatory T cells / high resolution image system / 胸腺 / SIVベクター / 抗第VIII因子インヒビター / 樹状細胞
Research Abstract

Hemophilia A is a congenital bleeding disorder caused by a deficiency of coagulation factor VIII. Approximately 30% of hemophilia A patients develop inhibitors against factor VIII following replacement therapy. We have previously reported that neonatal exposure of factor VIII antigen might induce antigen specific immune tolerance by IFN-γ dependent T cell anergy in hemophilic mice (Madoiwa S, et al. J Thromb Haemost 2:754-762,2004). Thymus plays crucial roles of self-tolerance with negative selection of self-reactive effector T cells and positive selection of self-reactive regulatory T cells. In this study, we focused on the induction of immune tolerance by direct thymic injection of factor VIII. Hemophilia mice were injected recombinant human factor VIII into thymus under the real time high resolution image guidance (Vevo 770, Visual Sonic Inc.). We measured the factor VIII inhibitors after repeated intravenous injection of factor VIII. The CD4+ cells, antigen presenting cells (APCs) and CD4+CD25+ cells were isolated for the proliferation and cytokine assays under in vitro stimulation of factor VIII. Anti-factor VIII inhibitory antibody titers were significantly lower in mice (n=17) with thymic injection of factor VIII than in mice (n=18) without injection (14.6 ± 3.8 vs 184.5 ± 48.6 Bethesda units/mL, respectively, p=0.0019). The CD4+ cells from thymic injected mice could not proliferate or produce IL-2, IL-12, and IFN-γ in response to factor VIII, when they were co-cultured with APCs from immunogenic mice. The CD4+CD25+ cells from thymic treated mice but not from naive mice efficiently suppressed the proliferative response of immunogenic mice derived CD4+ cells in the presence of APCs. Intrathymic administration of factor VIII could result in immune tolerance by factor VIII specific regulatory T cells induction. This immune tolerance model may provide a basis of new manipulation for the prevention of factor VIII inhibitors.

Report

(3 results)
  • 2006 Annual Research Report   Final Research Report Summary
  • 2005 Annual Research Report
  • Research Products

    (23 results)

All 2007 2006 2005

All Journal Article (23 results)

  • [Journal Article] Essential roles of sphingosine 1-phosphate/S1P1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury.2007

    • Author(s)
      Kimura A
    • Journal Title

      Stem Cells. 25(1)

      Pages: 115-124

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Annexin 2 and hemorrhagic disorder in vascular intimal carcinomatosis.2007

    • Author(s)
      Madoiwa S
    • Journal Title

      Thromb Res. 119(2)

      Pages: 229-240

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Essential roles of sphingosine 1-phosphate/SIP1 receptor axis in the migration of neural stem cells toward a site of spinal cord injury.2007

    • Author(s)
      Kimura A
    • Journal Title

      Stem Cells. 25(1)

      Pages: 115-124

    • Related Report
      2006 Annual Research Report
  • [Journal Article] 抗血管新生物質 : アンギオスタチンの最近の進歩2007

    • Author(s)
      窓岩清治
    • Journal Title

      Annual Review 血液 2007

      Pages: 281-281

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Plasminogen activator inhibitor 1 promotes a poor prognosis in sepsis-induced disseminated intravascular coagulation.2006

    • Author(s)
      Madoiwa S
    • Journal Title

      Int J Hematol. 84(5)

      Pages: 398-405

    • NAID

      10018670838

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Efficient expression of a transgene in platelets using simian immunodeficiency virus-based vector harboring glycoprotein Ibalpha promoter : in vivo model for platelet-targetine gene therapy.2006

    • Author(s)
      Ohmori T
    • Journal Title

      FASEB J. 20(9)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] A classification of the fibrin network structures formed from the hereditary dysfibrinogens.2006

    • Author(s)
      Sugo T
    • Journal Title

      J Thromb Haemost. 4(8)

      Pages: 1738-1746

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene.2006

    • Author(s)
      Ishiwata A
    • Journal Title

      Thromb Res. 118(5)

      Pages: 627-635

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients.2006

    • Author(s)
      Kimura R
    • Journal Title

      Blood 15;107(4)

      Pages: 1737-1738

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Utility of intraperitoneal administration as a route of AAV serotype 5 vector-mediated neonatal gene transfer.2006

    • Author(s)
      Ogura T
    • Journal Title

      J Gene Med. 8(8)

      Pages: 990-997

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity : involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients.2006

    • Author(s)
      Ohmori T
    • Journal Title

      J. Thromb. Haemost. (4)

      Pages: 1271-1278

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Acute sensorineural hearing loss and vertigo in a young adult with congenital plasminogen disorder.2006

    • Author(s)
      Ishida T
    • Journal Title

      Auris Nasus Larynx. (33)

      Pages: 187-190

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Severe secondary deficiency of von Willebrand factor-cleaving protease (ADAMTS13) in patients with sepsis-induced disseminated intravascular coagulation : Its correlation with development of renal failure.2006

    • Author(s)
      Ono T
    • Journal Title

      Blood 15:107(2)

      Pages: 528-534

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary 2005 Annual Research Report
  • [Journal Article] Efficient expression of a transgene in platelets using simian immunodeficiency virus-based vector harboring glycoprotein Ibalpha promoter : in vivo model for platelet-targeting gene therapy.2006

    • Author(s)
      Ohmori T
    • Journal Title

      FASEB J. 20(9)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Annual Research Report 2006 Final Research Report Summary
  • [Journal Article] Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients.2006

    • Author(s)
      Kimura R
    • Journal Title

      Blood. 15:107(4)

      Pages: 1737-1738

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Aspirin resistance detected with aggregometry cannot be explained by cyclooxygenase activity : involvement of other signaling pathway(s) in cardiovascular events of aspirin-treated patients.2006

    • Author(s)
      Ohmori T
    • Journal Title

      J.Thromb.Haemost. 4

      Pages: 1271-1278

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] Acute sensorineural hearing loss and vertigo in a young adult with congenital plasminogen disorder.2006

    • Author(s)
      Ishida T
    • Journal Title

      Auris Nasus Larynx. 33

      Pages: 187-190

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2006 Final Research Report Summary
  • [Journal Article] 凝固線溶反応 I生体侵略と生体反応 総論 特集 : 基礎から学ぶ侵襲と生体反応2006

    • Author(s)
      窓岩清治
    • Journal Title

      救急医学 30(9)

      Pages: 1015-1020

    • Related Report
      2006 Annual Research Report
  • [Journal Article] DIC の病態と線溶2006

    • Author(s)
      窓岩清治
    • Journal Title

      日本血栓止血学会誌 17(3)

      Pages: 254-260

    • NAID

      10021258761

    • Related Report
      2006 Annual Research Report
  • [Journal Article] Annexin 2 and hemorrhagic disorder in vascular intimal carcinomatosis.2006

    • Author(s)
      Madoiwa S
    • Journal Title

      Thromb Res.2006 Mar 6 ; [Epub ahead of print]

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Acute sensorineural hearing loss and vertigo in a young adult with congenital plasminogen disorder.2006

    • Author(s)
      Ishida T
    • Journal Title

      Auris Nasus Laynx.2006 Feb 22 ; [Epub ahead of print]

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Phenotype correction of hemophilia A mice with adeno-associated virus vectors carrying the B domain-deleted canine factor VIII gene.2006

    • Author(s)
      Ishiwata A
    • Journal Title

      Thromb Res.2005 Dec 18 ; [Epub ahead of print]

    • Related Report
      2005 Annual Research Report
  • [Journal Article] Protection of plasminogen activator inhibitor-1-deficient mice from nasal allergy.2005

    • Author(s)
      Sejima T
    • Journal Title

      J Immunol 174(12)

      Pages: 8135-8143

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2006 Final Research Report Summary 2005 Annual Research Report

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Published: 2005-04-01   Modified: 2016-04-21  

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