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STUDIES FOR TREATMENT OF HEMOPHILIA A WITH INHBITOR USING CANINIE SYSTEM

Research Project

Project/Area Number 06670819
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Pediatrics
Research InstitutionNARA MEDICAL UNIVERSITY

Principal Investigator

SHIMA Midori  NARA MEDICAL UNIVERSITY,PEDIATRICS,ASSOCIATE PROFESSOR, 医学部, 助教授 (30162663)

Co-Investigator(Kenkyū-buntansha) TANAKA Ichiro  NARA MEDICAL UNIVERSITY,PEDIATRICS,ASSISTANT PROFESSOR, 医学部, 講師 (00201616)
澤本 好克  奈良県立医科大学, 医学部, 助手 (10264863)
Project Period (FY) 1994 – 1996
Project Status Completed (Fiscal Year 1996)
Budget Amount *help
¥2,200,000 (Direct Cost: ¥2,200,000)
Fiscal Year 1996: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1995: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 1994: ¥700,000 (Direct Cost: ¥700,000)
Keywordshemophilia A / inhibitor / factor VIII / 抗第VIII因子同種抗体
Research Abstract

Using enzyme-linked immunosorbent assay (ELISA), we measured anti-factor JVIII immunoglobulin G (IgG), IgG4 and IgM in serum samples obtained from hemophilia A patients treated woth a recombinant factor VIII preparation. The correlation between the neutralizing activity and reactivity of the IgG4 antibody with factor VIII was high with correlation coefficients of 0.912.
We constructed a fusion protein, glutathione-C2, which binds to immobillized von Willebrand factor (vWF), suggesting that the factor VIII C2 domain contains a binding site for vWF.
Immunoblotting using a panel of recombinant light chain fragments demonstrated that the binding regions of antibodies in cases 1 to 5 were contained in the C2 domain of the light chain. Antibodies from cases 1 and 2, which recognised an epitope within residues 2248-2312, completely inhibited FVIII/vWF binding. Antibodies from case 3 recognising 2170-2312 and case 5 recognising 2170-2327 also inhibited FVIII/vWF binding. Case 4 antibodies recognising 2218-2307 showed barely detectable inhibition and cases 6 and 7 antibodies recognising the 44-kDa heavy chain, did not inhibit. Our results demonstrate that all anti-C2 alloantibodies with epitopes that extend to the residue 2312 inhibit vWF binding and that an overlap of the inhibitor epitope with residues 2308-2312 is critical. Synthetic peptides consisting of 15 residues inhibited factor VIII binding to vWF,phospholipid and anti-C2 inhibitor.
Caninie factor VIIII could act as cofactor in human system too. We tested reactivity of caninie factor VIII with several inhibitor alloantibodies. Inhibitor alloantiboies which recognized the C2 domain in the factor VIII light chain cross reacted well with canine factor VIII.On the other hand, inhibitors alloantibodies which recognized the A2 domain in the heavy chain did not react with caninie factor VIII.
We are going to administer the neutralyzing synthetic peptides to caninie model.

Report

(4 results)
  • 1996 Annual Research Report   Final Research Report Summary
  • 1995 Annual Research Report
  • 1994 Annual Research Report
  • Research Products

    (34 results)

All Other

All Publications (34 results)

  • [Publications] Seiki Kamisue: "Abnormal factor VIII Hiroshima:defect in crucial proteolytic cleavage by thrombin at Arg^<1689> detected by a novel ELISA" British Journal of Haematology. 86. 106-111 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Evgueni L Saenko: "A role for the C2 domain of factor VIII in binding to von Willebrand factor" Journal of Biological Chemistry. 269. 11601-11605 (1994)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Dorothea Scandella: "Some factor VIII inhibitor antibodies recoginze a common epitope corresponding to C2 domain amino acids 2248 through 2312,which overlap a phospholipid-binding site" Blood. 86. 1811-1819 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Midori Shima: "Measurement of anti-factor VIII IgG,IgG4 and IgM alloantibodies in previously untreated hemophilia A patients treated with recombinant factor VIII." International Journal of Hematology. 62. 35-43 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Midori Shima: "Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor." British Journal of Haematology. 91. 714-721 (1995)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Hideki Nagase: "Effect of depolymerized Holothurian glycosaminoglycan(DHG)on the activation of factor VIII and factor V by thrombin." The Journal of Biochemistry. 119. 63-69 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yoshikatu Sawamoto: "Measurement of anti-factor IX IgG subclasses in haemophilia B patients who developed inhibitors with epitopsodes of allergic reactions to factor IX concentrastes." Thrmbosis Research. 83. 279-286 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Evgueni Saenko: "Slowed release of thrombin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition." Jurnal of Biological Chemistry. 271. 27424-27431 (1996)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Yoshikatu Sawamoto: "Anti-factor VIII inhibitors alloantibodies recognizing A2 domain in the human factor VIII heavy chain poorly bind to porcine factor VIII." International Journal of Hematology. 65. 151-158 (1997)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Kamisue S,Shima M,Nishimura T,Tanaka I,Nakai H,Morichika S,Takata N,Kuramoto A,Yoshioka A: "Abnormal factor VIII Hiroshima : defect in crucial proteolytic cleavage by thrombin at Arg ^<1689> detected by a novel ELISA" British Journal of Haematology. 86. 106-111 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Saenko EL,SShima M,Rajalakshmi KJ,Scandella D: "A role for the C2 domain of factor VIII in binding to von Willebrand factor" Journal of Biological Chemistry. 269. 11601-11605 (1994)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Scandella D,Gilbert GE,Shima M,Nakai H,Eagleson C,Felch M,Prescott RM,Rajalakshmi KJ,Hoyer LW,Saenko EL: "Some factor VIII inhibitor antibodies recognize a common epitope corresponding to C2 domain amino acids 2248 through 2312, which overlap a phospholipid-binding site" Blood. 86. 1811-1819 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Shima M,Sawamoto Y,Nakai H,Kamisue S,Murakami T,Morichika S,Tanaka I,Hayashi K,Yoshioka A: "Measurement of anti-factor VIII IgG4 and IgM alloantibodies in previously untreated hemophilia A patients treated with recombinant factor VIII" International Journal of Hematology. 62. 35-43 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Shima M,Nakai H,Tanaka I,Sawamoto Y,Kamisue S,Morichika S,Murakami T,Yoshioka A: "Common inhibitory effects of human anti-C2 domain inhibitor alloantibodies on factor VIII binding to von Willebrand factor" British Journal of Haematology. 91. 714-721 (1995)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Nagase H,Enjyoji K,Shima M,Kitazato K,Yoshioka A,Saito H,Kato H: "Effect of depolymerized Holothurian glycosaminoglycan (DHG) on the activation of factor VIII and factor V by thrombin" The Journal of Biochemistry. 119. 63-69 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sawamoto Y,Shima M,Yamamoto M,Kamisue S,Nakai H,Tanaka I,Hayashi K,Giddings JC,Yoshioka A: "Measurement of anti-factor IX IgG subclasses in haemophilia B patients who developed inhibitors with epitopsodes of allergic reactions to factor IX concentrastes" Thrombosis Research. 83. 279-286 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Saenko E,Shima M,Gilbert GE,Scandella D: "Slowed release of thrombin-cleaved factor VIII from von Willebrand factor by a monoclonal and a human antibody is a novel mechanism for factor VIII inhibition" Jurnal of Biological Chemistry. 271. 27424-27431 (1996)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] Sawamoto Y,Shima Mi, Tanaka I,Nakai H,Kamisue S,Scandella D,Yoshioka A: "Anti-factor VIII inhibitors alloantibodies recognizing A2 domain in the human factor VIII heavy chain poorly bind to porcine factor VIII" International Journal of Hematology. 65. 151-158 (1997)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      1996 Final Research Report Summary
  • [Publications] SuzuKi H: "Factor VIII Ise (R215%) in a PatienC with mila hemophilia A, an absormal factor VIII with retention of tunction but modification of C2 epitopes." Thrombosis and Itaemostasis. 76 (in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sawamoto Y: "Anti-factor VIII inhibitor alloantibodies recognizing the A2 domain in the human factor VIII heour chain poorly bind to porcine factor VIII." International Journal of Hematolosy. 64 (in press). (1997)

    • Related Report
      1996 Annual Research Report
  • [Publications] Saenko E: "Slowed release of thrombin-c leaved foctor VIII tram van Willebrand factor by a monoclonal and a human antibody isa novel mechanism for factor VIII inhibition." Journal of Biological Chemistry. 271. 27424-27431 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Sawamoto Y: "Mcasurement of anti-factor 1x IgG sabclass in haemophiloa patiencs who developed inhibitors with episodes of a hergk reactons to factor 1x concentrates." Thrombosis Research. 83. 279-286 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Yoshioka A: "Thromboe lastgram as a hemostatic manicoring during recombinant factor the theatment in hemophilia A patients with inhibitor to factor VIII." Haemostasis. 26. 139-142 (1996)

    • Related Report
      1996 Annual Research Report
  • [Publications] Shima M.: "Common inhibitory effect of human anti-C2 domain inhibitor alloantibonies an factor VIII b,nding to von willebrund fuctor" British Journal of Haematology. 91. 714-721 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Shima M.: "Measurement of anti-tactor VIII IgG,IgG_4 and IgM allcan Ghodres in preuonsly untreated hemophilia A patents treated with reconbinant factor VIII" International Journal of Hematology. 62. 35-43 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Scandella D.: "Some factor VIII inhibitor untibodies recoynige a common epitopecorespondny to C2 domain amino acid 2248 throgh 2312,which overlap a phasp holipid binding site" Blood. 86. 1811-1819 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Nagase H.: "Effect of depolynerized nolothurian glycosaminoglycan(UMG) on the activation of factor VIII and factor V by Chrombn" Journal of Biochemistry. 119. 63-69 (1996)

    • Related Report
      1995 Annual Research Report
  • [Publications] 嶋 緑倫: "臨床DNA診断法" 金原出版, 1134 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] 嶋 緑倫: "遺伝子病マニュアル 上" 中山書店, 425 (1995)

    • Related Report
      1995 Annual Research Report
  • [Publications] Saenko EL: "A role for the C2 domain of tactor VIII in binding to von willebrand factor" Jounal of Biological Chemistry. 263. 11601-11605 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Yoshioka A: "The use of poroine factor VIII in Japan" Seminar in Hematology. 31. 26-28 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] Kamisue S: "Abnormal factor VIII Hiroshima:cletect in crucial protealy LC ckavage by thronbinat Arg 1689 detected by a novel ELISA" British Journal of Hematology. 86. 106-111 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 嶋 緑倫: "血液病学" 文光堂, 1813 (1994)

    • Related Report
      1994 Annual Research Report
  • [Publications] 嶋 緑倫: "止血・血栓・線溶" 中外医学社, 500 (1994)

    • Related Report
      1994 Annual Research Report

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Published: 1994-04-01   Modified: 2016-04-21  

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