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Molecular pathogenesis of bone marrow failure as a major cause of death in paroxysmal nocturnal hemoglobinuria

Research Project

Project/Area Number 18591081
Research Category

Grant-in-Aid for Scientific Research (C)

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

Principal Investigator

NAKAUMA Hideki  Wakayama Medical University, Faculty of Medicine, Professor (90207746)

Co-Investigator(Kenkyū-buntansha) SONOKI Takashi  Wakayama Medical University, 医学部, Associate Professor (30382336)
KAWAGUCHI Tatsuya  Kumamoto University Hospital, 医学部・附属病院, Associate Professor (50244116)
Project Period (FY) 2006 – 2007
Project Status Completed (Fiscal Year 2007)
Budget Amount *help
¥3,890,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥390,000)
Fiscal Year 2007: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2006: ¥2,200,000 (Direct Cost: ¥2,200,000)
Keywordsparoxysmal nocturnal hemoglobinuria / aplastic anemia / bone marrow failure / NKG2D / NKG2D ligands / ULBP / MICA / B / stress-inducible proteins / 造血不全
Research Abstract

The prevalence of aplastic anemia and paroxysmal nocturnal hemoglobinuria (PNH) that manifest fatal marrow failure are relatively high in Japan. The marrow failure shows good response to immunosuppressive therapy, indicating that marrow failure is immune-mediated. However, the pathogenesis including molecular targets on hematopoietic cells recognized by lymphocytes is unknown yet.
In the present study, we show both that stress-inducible membrane proteins (or NKG2D ligands) such as ULBP and MICA/B were pathologically expressed on granulocytes and bone marrow CD34+ cells of patients with PNH and aplastic anemia, and that the granulocytes were injured by autologous lymphocytes dependently on the ligand expression in vitro (Hanaoka, et. al., Blood 2006). We then propose that the ligands are the molecular targets for lymphocytes in immune-mediated impairment of hemotopoiesis in the marrow failure syndromes such as PNH and aplastic anemia. lb support the hypothesis, we prospectively analyzed the clinical courses for one up to five years of 3 patients with aplastic anemia-PNH syndromes and 2 patients with aplastic anemia. We then found that one or more of the sress-inducible NKG2D ligands were expressed on their granulocytes. The expression closely associated not only with pancytbpenia reflecting marrow failure, but also with a favorable response of marrow failure to immunosuppressive therapy.
We thus conclude that at least a part of patients with idiopathic bone marrow failure syndromes including PNH and aplastic anemia are exposed to a certain stress to induce the NKG2D ligands on their blood cells and that the ligand expression triggers off or promotes the NKG2D-mediated blood cell injury by autologous lymphocytes, leading to marrow failure (Kawaguchi & Nakakuma, Int J Hematol 2007). Currently, we are confirming the NKG2D-mediated marrow cells injury by in vitro colony formation inhibition assays with antibodies to NKG2D and its ligands.

Report

(3 results)
  • 2007 Annual Research Report   Final Research Report Summary
  • 2006 Annual Research Report
  • Research Products

    (8 results)

All 2007 2006

All Journal Article (5 results) (of which Peer Reviewed: 3 results) Presentation (3 results)

  • [Journal Article] New insights into molecular pathogenesis of bone marrow failure in paroxysmal nocturnal hemoglogbinuria2007

    • Author(s)
      Kawaguchi T, Nakakuma H
    • Journal Title

      International Journal of Hematology 86

      Pages: 27-32

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] New insights into molecular pathogenesis of bone marrow failure in paroxysmal nocturnal hemoglobinuria2007

    • Author(s)
      Kawaguchi T, Nakakuma, H
    • Journal Title

      Int J Hematol 86

      Pages: 27-32

    • NAID

      10018515469

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Journal Article] New insights into molecular pathogenesis of bone marrow failure in paroxysmal noctumal hemoglogbinuria.2007

    • Author(s)
      Kawaguchi T
    • Journal Title

      International Journal of Hematology 86

      Pages: 27-32

    • Related Report
      2007 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP2006

    • Author(s)
      Hanaoka N, et. al.
    • Journal Title

      Blood 107

      Pages: 1184-1191

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Final Research Report Summary
    • Peer Reviewed
  • [Journal Article] Immunoselection by natural killer cells of PIGA mutant cells missing stress-inducible ULBP2006

    • Author(s)
      Hanaoka et al.
    • Journal Title

      Blood 107

      Pages: 1184-1191

    • Related Report
      2006 Annual Research Report
  • [Presentation] PNHおよび関連疾患におけるNKG2D介在性の造血障害2007

    • Author(s)
      花岡 伸佳、中熊 秀喜, 他5名
    • Organizer
      第69回日本血液学会・第49回日本臨床血液学会合同総会
    • Place of Presentation
      横浜
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2007 Annual Research Report 2007 Final Research Report Summary
  • [Presentation] NKG2D-mediated marrow injury in paroxysmal nocturnal hemoglobinuria and its related disorders2007

    • Author(s)
      Hanaoka N, et. al.
    • Organizer
      The joint meeting of the 69th Annual Meeting of Japanese Society of Hematology and the 49th Annual Meeting of Japanese Society of Clinical Hematology
    • Place of Presentation
      Yokohama
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary
  • [Presentation] NKG2D-mediated marrow injury in paroxysmal nocturnal hemoglobinuria and its related disorders2007

    • Author(s)
      Hanaoka N, et. al.
    • Organizer
      The 49th Annual Meeting of American Society of Hematology
    • Place of Presentation
      Atlanta, GA
    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2007 Final Research Report Summary

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Published: 2006-04-01   Modified: 2016-04-21  

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