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Etiology for idiopathic pulmonary alveolar proteinosis : Roles of the autoantibody against GM-CSF in the pathogenesis.

Research Project

Project/Area Number 13670624
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeSingle-year Grants
Section一般
Research Field Respiratory organ internal medicine
Research InstitutionResearch Institute, International Medical Center of Japan

Principal Investigator

NAKATA Koh  International Medical Center of Japan, Medical and dental Hospital, Professor, 呼吸器疾患研究部, 室長 (80207802)

Co-Investigator(Kenkyū-buntansha) KEICHO Naohito  International Medical Center of Japan, 呼吸器疾患研究部, 部長 (80332386)
Project Period (FY) 2001 – 2003
Project Status Completed (Fiscal Year 2003)
Budget Amount *help
¥3,900,000 (Direct Cost: ¥3,900,000)
Fiscal Year 2003: ¥800,000 (Direct Cost: ¥800,000)
Fiscal Year 2002: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2001: ¥1,600,000 (Direct Cost: ¥1,600,000)
Keywordspulmonary alveolar proteinosis / granulocyte macrophage colony stimulating factor / alveolar macrophage / lung surfactant / bronchoalveolar lavage / autoantibody / cytokine / autoimmune disease / 自己抗体 / サーファクタント / エピトープ / 自己抵抗
Research Abstract

Mice deficient in either GM-CSF or its receptor develop pulmonary alveolar proteinosis (PAP), which is a diseases characterized by accumulation of excessive surfactant composed of phospholipids and surfactant proteins in the alveoli and terminal bronchioli, pointing to a role for GM-CSF in the pathogenesis of PAP. Thus, in this model, lack of GM-CSF signaling produces AM dysfunction leading to PAP. This conclusion is strongly supported by the observation that PAP in the receptor knockout mouse was corrected by bone marrow transplantation from wild type mice and PAP in the cytokine knock out mouse was corrected by transgenic expression of GM-CSF in the pulmonary epithelia. The relationship of the mouse model of PAP to human idiopathic PAP, the most common acquired form of unknown etiology, remains to be elucidated. Recently, we found a factor in the bronchoalveolar lavage fluid (BALF) from IPAP patients that neutralizes the bioactivity of GM-CSF. The factor directly binds to GM-CSF and blocks the binding to GM -CSF receptor on cells. Here, we describe that the factor is a neutralizing auto-antibody directed against GM-CSF in the BALF and sera of patients with IPAP. Our data suggest that IPAP patients have disruption of GM-CSF signaling similar to the mouse model of PAP. In the human disease, however, GM-CSF signaling is abolished by a neutralizing auto-antibody. These findings may promote a rational development of future therapies to lower levels of auto-antibody against GM-CSF in the lung in IPAP patients.

Report

(4 results)
  • 2003 Annual Research Report   Final Research Report Summary
  • 2002 Annual Research Report
  • 2001 Annual Research Report
  • Research Products

    (35 results)

All 2004 2003 2002 Other

All Journal Article (13 results) Book (1 results) Publications (21 results)

  • [Journal Article] High Affinity Autoantibodies Specifically Eliminate Granulocyte-Macrophage Colony-StimulatingFactor Activity In The Lungs Of Patients With Idiopathic Pulmonary Alveolar Proteinosis2004

    • Author(s)
      Kenji Uchida, Koh Nakata, Bruce C.Trapnell.Takahiro Terakawa, Emi Hamano, Ayako Mikami, Ikumi Matsushita, John F.Seymour, Masayoshi Oh-eda, Ikuo Ishige, Yoshinobu Eishi, Takayuki Kitamura, Yoshitsugu Yamada, Kazuo Hanaok
    • Journal Title

      BLOOD 103

      Pages: 1089-1098

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and LDH to pulmonary parameters and respo〓2003

    • Author(s)
      Seymour JF, Doyle IR, Nakata K, Presneil IJ, AR Dunn
    • Journal Title

      Thorax 57

      Pages: 252-257

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Secondary alveolar proteinosis associated with myelodysplastic syndrome2003

    • Author(s)
      Ohnishi T, Yamada G, Shijubo, N, Takagi Y, Itoh T, Nakata K〓
    • Journal Title

      Internal Medicine 42(2)

      Pages: 187-190

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Successful recombinant GM-CSF treatment of pulmonary alveolar proteinosis (PAP) in a patient without anti-GM-CSF antibodies2003

    • Author(s)
      F Khanjari, H Watier, J Domenech E, Asquier, P Diot
    • Journal Title

      Thorax 58

      Pages: 645-645

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] 日本胸部臨床2003

    • Author(s)
      中田 光
    • Journal Title

      日本胸部臨床 62

      Pages: 197-203

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] 特発性肺胞蛋白症におけるGM-CSF吸入療法2003

    • Author(s)
      中田 光
    • Journal Title

      呼吸と循環 51

      Pages: 1027-1030

    • NAID

      40019999933

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Relationship of anti-GM-CSF antibodyconcentration, surfactant protein A and B levels, and LDH to pulmonary parameters and response to GM-CSF therapy in patientsn with idiopathic alveolar proteinosis.2003

    • Author(s)
      Seymour JF, Doyle IR, Nakata K, Presneil IJ, AR Dunn
    • Journal Title

      Thorax 57

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Pulmonary Alveolar Proteinosis ; Mechanism of Disease.2003

    • Author(s)
      Trapnell B, Whitsett J, Nakata K.
    • Journal Title

      NewEngland Journal of Medicine. 349

      Pages: 2528-40

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Secondary alveolar proteinosis associated with myelodysplastic syndrome2003

    • Author(s)
      Ohnishi T, Yamada G, Shijubo, N, Takagi Y, Itoh T, Nakata K, Abe S.
    • Journal Title

      Internal Medicine 42(2)

      Pages: 187-190

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Successful recombinant GM-CSF treatment of pulmonary alveolar proteinosis (PAP) in a patient without anti-GM-CSF antibodies2003

    • Author(s)
      F Khanjari, H Watier, J Domenech, E Asquier, P Diot, K Nakata
    • Journal Title

      Thorax 58

      Pages: 645-645

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines.2002

    • Author(s)
      Hoshino Y, Nakata K, Hoshino S, Honda Y, Tse D, Shioda T, Rom W, Micahel Weiden
    • Journal Title

      J.Exp.Med. 195

      Pages: 495-505

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Bronchoalveolar lavage findings in pulmonary alveolar proteinosis successfully treated with GM-CSF,2002

    • Author(s)
      Schoch OD, Schanz U, Koller M, Nakata K, Seymour JF, Russi EW, Boehler A.
    • Journal Title

      Thorax 57

      Pages: 277-280

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Journal Article] Oligoclonal T cell expansions in pulmonary lymphoproliferative disorders : demonstration of the frequent occurrence of oligoclonal T cells in human immunodeficiency virus-related lymphoid interstitial pneumonia.2002

    • Author(s)
      Kurosu K, Yumoto N, Rom WN, Takiguchi Y, Jaishree J, Nakata K, Tatsumi K, Mikata A, Kuriyama T, Weiden MD.
    • Journal Title

      Am J Respir Crit Care Med. 165

      Pages: 254-258

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Book] 感染・発病・進展の病理、エイズ合併結核2003

    • Author(s)
      中田 光(分担執筆)
    • Total Pages
      150
    • Publisher
      新企画出版
    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2003 Final Research Report Summary
  • [Publications] Seymour SF, Doyle IR, Nakata K, Presneil IJ, AR Dunn: "Relationship of anti-GM-CSF antibody concentration, surfactant protein A and B levels, and LDH to pulmonary parameters and response to GM-CSF therapy in patients with idiopathic alveolar proteinosis"Thorax. 57. 252-257 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Ohinshi T, Yamada G, Shijubo, N, Takagi Y, Itoh T, Nakata K: "Secondary alveolar proteinosis associated with myelodysplastic syndrome"Internal Medicine. 42(2). 187-190 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] F Khanjari, H Watier, J Domenech, E Asquier, P Diot, K Nakata: "Successful recombinant GM-CSF treatment of pulmonary alveolar proteinosis (PAP)in a patient without anti-GM-CSF antibodies"Thorax. 58. 645 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Kanji Uchida, Koh Nakata, Bruce C.Trapnell, Takahiro Terakawa, Emi Hamano, Ayako Mikami, Ikumi Matsushita, John F.Seymour, Masayoshi Oh-eda, Ikuo Ishige, Yoshinobu Eishi, Takayuki Kitamura, Yoshitusugu Yamada, kazuo Hnaoka: "High Affinity Autoantibodies Specifically Eliminate Granulocyte-Macrophage Colony-Stimulating Factor Activity In The Lungs Of Patients With Idiopathic Pulmonary Alveolar Proteinosis"BLOOD. 103. 1089-1098 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中田 光: "日本胸部臨床"日本胸部臨床. 62. 197-203 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中田 光: "特発性肺胞蛋白症におけるGM-CSF吸入療法"呼吸と循環. 51. 1027-1030 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] 中田 光(分担執筆): "感染・発病・進展の病理、エイズ合併結核"新企画出版. 150 (2003)

    • Related Report
      2003 Annual Research Report
  • [Publications] Trapnell B, Whitsett J, Nakata K: "Pulmonary Alveolar Proteinosis ; Mechanism of Disease"New England Journal of Medicine.. (in press). (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Ohnishi T, Yamada G, Shijubo, N, akagi Y, Itoh T, Nakata K, Abe S: "Secondary alveolar proteinosis associated with myelodysplastic syndrome"Internal Medicine. 42(2). 187-190 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Seymour JF, Doyle IR, Nakata K, Presneil IJ, AR Dunn: "Relationship of anti-GM-CSF antibodyconcentration, surfactant protein A and B levels, and LDH to pulmonary parameters and response to GM-CSF therapy in patientsn with idiopathic alveolar proteinosis"Thorax. 58. 252-257 (2003)

    • Related Report
      2002 Annual Research Report
  • [Publications] Hoshino Y, Nakata K, Hoshino S, Honda Y, Tse D, Shioda T, Rom W, Micahel Weiden: "Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines"Journal of Experimental. Medicine. 195. 495-505 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Kurosu K, Yumoto N, Rom WN, Takiguchi Y, Jaishree I, Nakata K, Tatsumi K, Mikata: "Oligoclonal T cell expansions in pulmonary lymphoproliferative disorders : demonstration of the frequent occurrence of oligoclonal T cells in human immunodeficiency virus-related lymphoid interstitial pneumonia"American Journal of Respiratory and Critical Care Medicine.. 165(2). 254-259 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Schoch GD, Schanz U, Koller M, Nakata, Seymour JF, Russi EW, Boehier A.: "Bronchoalveolar lavage findings in pulmonary alveolar proteinosis successfully treated with GM-CSF"Thorax. 57. 277-280 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] 吉山崇, 森亨, 中田光, 藤田明, 永井英明: "エイズ合併結核、感染・発病・進展の病理、、36-77"新企画出版社. 160 (2002)

    • Related Report
      2002 Annual Research Report
  • [Publications] Seymour JF, Presneill JJ, Schoch OD, Nakata K.: "Therapeutic Efficacy of Granulocyte-Macrophage Colony-Stimulating Factor in Patients with Idiopathic Acquired Alveolar Proteinosis"American Journal Respiratory Critical Care Medicine. 163. 524-531 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hirota M, Totsu T, Adachi F, Nakata K.: "Comparison of antimycobacterial activity of grepafloxacin against Mycobacterium avium with that of levofloxacin : Accumulation of grepafloxacin in human macrophages"Journal of Infection and Chemotherapy. 163. 16-21 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Keicho N, Emi M, Kajita M, Matsushita I, Nakata K: "Overestimated frequency of a possible emphysema-susceptibility allele when microsomal epoxide hydrolase is genotyped by the conventional polymerase chain reaction-based method"Journal of Human Genetics. 46. 96-98 (2001)

    • Related Report
      2001 Annual Research Report
  • [Publications] Kurosu K, Rom WN, Nakata K: "Oligoclonal T cell expansions in pulmonary lymphoproliferative disorders: demonstration of the frequent occurrence of oligoclonal T cells in human immunodeficiency virus-related lynphoid interstitial pneumonia"American Journal Respiratory Critical Care Medicine. 165. 254-259 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Schoch OD, Schanz U, Koller M, Nakata K, Seymour JF, Russi EW: "Bronchoalveolar larage findings in pulmonary alveolar proteinosis successfully treated with GM-CSF."Thorax. 57. 277-280 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] Hoshino, Y, Nakata K, Row W, Micahel Weiden:: "Maximal HIV-1 replication in alveolar macrophages during tuberculosis requires both lymphocyte contact and cytokines"Journal of Experimental Medicine. 195. 495-505 (2002)

    • Related Report
      2001 Annual Research Report
  • [Publications] 中田 光, 本田芳裕: "HIV と結核の相互作用の分子機構、「結核」"編集 光山正雄、大阪、医薬ジャーナル社. 414 (2001)

    • Related Report
      2001 Annual Research Report

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

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