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MECHANISM FOR SELECTIVE EXPANSION OF A PIG-A MUTANT IN PAROXYSMAL NOCTURNAL HEMOGLOBINEMIA

Research Project

Project/Area Number 13671070
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Hematology
Research InstitutionKUMAMOTO UNIVERSITY

Principal Investigator

KAWAGUCHI Tatsuya  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE, KOSHI (ASSISTANT PROFESSOR), 医学部附属病院, 講師 (50244116)

Co-Investigator(Kenkyū-buntansha) NAGAKURA Shoich  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE, CLINICAL STUFF, 医学部附属病院, 医員
ISHIHARA Sonoko  KUMAMOTO UNIVERSITY SCHOOL OF MEDICINE, CLINICAL STUFF, 医学部附属病院, 医員
Project Period (FY) 2001 – 2002
Project Status Completed (Fiscal Year 2002)
Budget Amount *help
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2002: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2001: ¥1,900,000 (Direct Cost: ¥1,900,000)
KeywordsParoxysmal nocturnal hemoglobinuria / PIG-A gene / bone marrow failure / glycosylphosphatidylinositol (GPI)-anchored proteins / natural killer cells / clonal expansion / Paroxysmal nocturnal hemoglobinuria / PIG-A mutation / Clonal expansion / Natural killer cell / GPI-anchored protein
Research Abstract

Paroxysmal nocturnal hemoglobinuria (PNH) is a hematopoietic stem cell disease characterized by hemolysis, venous thrombosis and marrow failure. A mechanism of hemolysis has been only elucidated. PNH cells lack glycosylphosphatidylinositol-anchored proteins (GPI-AP) including compliment regulatory proteins such as DAF and CD59, leading to increased sensitivity of erythrocytes to the lytic action of complement. The deficiency is caused by a somatic mutation of the PIG-A gene. Our current major concern is the mechanism by which a PNH clone expands. Increasing evidence has been shown that the presence of the mutation alone does not induce the expansion. To explain this issue, two hypotheses are proposed: a growth or a survival advantage theory. The latter indicates that PNH cells escape immune attack in the setting of immune-mediated bone marrow injury often observed in PNH patients. The present study was aimed to prove this hypothesis by verifying the escape mechanism in vitro.
We first p … More repared GPI-AP-deficient cell lines and control counterparts fully recovered with the expression of GPI-AP by transfection of PIG-A cDNA, and examined the sensitivity of these cells to killing by natural killer (NK) cells using ^<51>Cr-release assay. To both primary and cultured NK cells, GPI-AP-deficient cells were less susceptible than their control counterparts. NK activity was completely abolished with concanamycin A and by calcium chelation, indicating that killing was preforin-dependent. There were no differences in major histocompatibility classes I expression or sensitivity to either purified perforin or to interleukin-2-activated NK cells between GPI-AP-deficient cells and control cells. From these results we infer that GPI-AP-deficient cells lack molecules needed for NK activation or to trigger perforin-medicated killing. Our experiments suggest that PIG-A mutations confer a relative survival advantage to a PNH clone, contributing to selective expansion of these cells in the setting of marrow injury by cytotoxic lymphocytes. (296 words) Less

Report

(3 results)
  • 2002 Annual Research Report   Final Research Report Summary
  • 2001 Annual Research Report
  • Research Products

    (17 results)

All Other

All Publications (17 results)

  • [Publications] Horikawa, K., Kawaguchi, T., et al.: "Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal mocturnal hemoglobinuria"Blood. 99. 24-29 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 川口辰哉 他2名: "定量的PCRによる新しい遺伝子発現プロファイルシステムの構築 ー臨床および創薬への応用ー"Drug Delivery System. 17. 119-126 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagakura, S., Ishihara, S., et al.: "Decresed susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro"Blood. 100. 1031-1037 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 川口辰哉, 中熊秀喜: "PNHの発症をもたらす変異クローンの拡大機序"血液フロンティア. 12. 1037-1045 (2002)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] 堀川健太郎, 川口辰哉, 中熊秀喜: "発作性夜間血色素尿症(PNH)における変異易発生の造血環境. In : Annual Review 2003 血液 (編集 高久史麿 他)"中外医学社. 240 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nakakuma, H., Kawaguchi, T: "PNH clone acquires both a survival and a growth advantage? In : Paroxysmal nocturnal hemoglobinuria and related disorders. Molecular aspects of pathogenesis. (eds. Omine M, Kinoshita T.)"Springer-Verlag Tokyo. 285 (2003)

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Horikawa, K., Kawaguchi, T., et al.: "Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal nocturnal hemoglobinuria"Blood. 99. 24-29 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagakura, S., Ishihara, S., et al.: "Decreased susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro"Blood. 100. 1031-1037 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Kawaguchi, T., Cheronis, J., et al.: "A novel gene expression profiling system using quantitative PCR - For clinical research and drug development -"Drug Delivery System. 17. 119-126 (2002)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Nagakura, S., Kawaguchi, T., eds. Omine M, Kinoshita T.: "PNH clone acquires both a survival and a growth advantage?, in Paroxysmal nocturnal hemoglobinuria and related disorders. Molecular aspects of pathogenesis"Springer-Verlag. 97-103 (2003)

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2002 Final Research Report Summary
  • [Publications] Horikawa, K., Kawaguchi, T., et al.: "Frequent detection of T cells with mutations of the hypoxanthine-guanine phosphoribosyl transferase gene in patients with paroxysmal nocturnal hemoglobinuria"Blood. 99. 24-29 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 川口辰也, 他2名: "定量的PCRによる新しい遺伝子発現プロファイルシステムの構築-臨床および創薬への応用-"Drug Delivery System. 17. 119-126 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nagakura, S., Ishihara, S., et al.: "Decresed susceptibility of leukemic cells with PIG-A mutation to natural killer cells in vitro"Blood. 100. 1031-1037 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 川口辰也, 中熊秀喜: "PNHの発症をもたらす変異クローンの拡大機序"血液フロンティア. 12. 1037-1045 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 堀川健太郎, 川口辰也, 中熊秀喜: "発作性夜間血色素尿症(PNH)における変異易発生の造血環境.In : Annual Review 2003血液(編集 高久史麿 他)"中外医学社. 240 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Nakakuma, H., Kawaguchi, T: "PNH clone acquires both a survival and a growth advantage? In : Paroxysmal nocturnal hemoglobinuria and related disorders. Moleculr aspects of pathogenesis. (eds. Omine M, Kinoshita T.)"Springer-Verlag Tokyo. 285 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Horikawa, K., Kawaguchi, T., et al.: "Frequent detection of T cells with mutations of the hypoxanthine-guanine phos-phoribosyl transferase gene in patients with paroxymal nocturnal hemoglobinuria"Blood. 99. 24-29 (2002)

    • Related Report
      2001 Annual Research Report

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Published: 2001-04-01   Modified: 2016-04-21  

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