A systematic research on immunomodulation in autoimmune pulumonary alveolar proteinpsis.

• Project/Area Number: 20390230
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Respiratory organ internal medicine
• Research Institution: Niigata University
• Principal Investigator: NAKATA Koh Niigata University, 医歯学総合病院, 教授 (80207802)
• Co-Investigator(Kenkyū-buntansha): TAZAWA Ryushi 新潟大学, 医歯学総合病院, 講師 (70301041) ; TAKIZAWA Jun 新潟大学, 医歯学系, 助教 (70463990)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥19,240,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥4,440,000); Fiscal Year 2010: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2009: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000); Fiscal Year 2008: ¥13,780,000 (Direct Cost: ¥10,600,000、Indirect Cost: ¥3,180,000)
• Keywords: 非閉塞性肺疾患癌 / 肺線維症 / 呼吸器感染症 / その他 / 肺胞蛋白症 / GM-CSF / T-リンパ球 / PDLD / 自己抗体 / 自己免疫性肺胞蛋白症 / 抗GM-CSF抗体 / アイソタイプ / EBウイルス / メモリーB細胞 / ELISPOT / 抗GM-CSF自己抗体 / リンパ球サブセット / T細胞 / アポトーシス / B細胞分化

Research Abstract

High avidity GM-CSF autoantibodies (GMAb) with IgG isotype are now considered to be the etiology for autoimmune pulmonary alveolar proteinsosis (aPAP). We detected low concentrations of IgM-GMAb in more than 80% of 71 aPAP patients and 22% of 23 healthy subjects. The frequencies and concentrations of IgM type in culture supernatants were even between aPAP and controls. In contrast, the frequency of IgG-GMAb producing B cells was higher in aPAP than those in controls. The present results suggest that the isotype switch from IgM to IgG is accelerated in patients with aPAP.

Research Products

• [Journal Article] Clinical features of secondary pulmonary alveolar proteinosis : pre-mortem cases in Japan. (2011)
  • Author(s): Ishii H, Tazawa R (10人略), Nakata K.
  • Journal Title: European Respir. J. Vol.37, No.2 Pages: 465-468
  • Peer Reviewed
• [Journal Article] Clinical features of secondary pulmonary alveolar proteinosis : pre-mortem cases in Japan. (2011)
  • Author(s): Ishii H, Tazawa R(10人略), Nakata K.
  • Journal Title: European Respir.J Volume: Vol.37 No.2 Pages: 465-468
  • Peer Reviewed
• [Journal Article] Adult-onset hereditary pulmonary alveolar proteinsosis caused by a single-base deletion in CSF2RB. (2010)
  • Author(s): Tanaka T, Motoi N, Tsuchihashi Y, Tazawa R (8人略) Nakata K, Morimoto K.
  • Journal Title: J.Med. Genetics 10巻 Pages: 1136-1141
  • Peer Reviewed
• [Journal Article] 大規模臨床試験の現状と展望 (2010)
  • Author(s): 中田光
  • Journal Title: 呼吸と循環 Vol.58, No.12 Pages: 1233-1240
  • Peer Reviewed
• [Journal Article] GM-CSF Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Non-human Primates. (2010)
  • Author(s): Sakagami T,(6人略)Nakata K, (5人略), Trapnell BC.
  • Journal Title: Am J Respir Crit Care Med. 182(1)巻 Pages: 49-61
  • Peer Reviewed
• [Journal Article] 稀少疾患をどう克服するか?-国際コンソーシアムの試み- (2010)
  • Author(s): 中田光、田澤立之
  • Journal Title: THE LUNG perspectives別冊 Vol.18, No.2 Pages: 129-132
  • Peer Reviewed
• [Journal Article] Inhaled Granulocyte/Macrophage-Colony Stimulating Factor as Therapy of Pulmonary Alveolar Proteinosis. (2010)
  • Author(s): Tazawa R, Trapnell BC,(23人略)、Nakata K(corresponding author).
  • Journal Title: Am J Respir Crit Care Med. 181(12)巻 Pages: 1345-54
  • Peer Reviewed
• [Journal Article] 呼吸器疾患感受性-遺伝的背景-肺胞蛋白症 (2010)
  • Author(s): 田澤立之、中田光
  • Journal Title: 日本胸部臨床 69(8)巻 Pages: 735-740
  • Peer Reviewed
• [Journal Article] A cell free assay to estimate the neutralizing capacity of granulocyte-macrophage colony-stimulating factor autoantibodies. (2010)
  • Author(s): Urano S,(8人略), Nakata K(corresponding author).
  • Journal Title: J Immunol. Methods. 360(1-2)巻 Pages: 141-148
  • Peer Reviewed
• [Journal Article] High avidity cytokine autoantibodies in health and disease : Pathogenesis and Mechanisms. (2010)
  • Author(s): Watanabe M, Uchida K, Nakagaki K, Trapnell BC, Nakata K.
  • Journal Title: Cytokine & Growth Factor Reviews. Volume 21, Issue 4 Pages: 263-273
  • Peer Reviewed
• [Journal Article] Pulmonary alveolar proteinosis associated with dust inhalation : not secondary but autoimmune? (2010)
  • Author(s): Costabel U, Nakata K.
  • Journal Title: Am J Respir Crit Care Med. 180巻 Pages: 427-428
  • Peer Reviewed
• [Journal Article] Adult-onset hereditary pulmonary alveolar proteinsosis caused by a single-base deletion in CSF2RB. (2010)
  • Author(s): Tanaka T, Motoi N, TsuchihashiY, Tazawa R, (8人略) Nakata K, Morimoto K.
  • Journal Title: J Med.Genetics Volume: 10 Pages: 1136-1141
• [Journal Article] 大規模臨床試験の現状と展望 (2010)
  • Author(s): 中田光
  • Journal Title: 呼吸と循環 Volume: Vol.58 No.12 Pages: 1233-1240
  • Peer Reviewed
• [Journal Article] High avidity cytokine autoantibodies in health and disease : Pathogenesis and Mechanisms. (2010)
  • Author(s): Watanabe M, Uchida K, Nakagaki K, Trapnell BC, Nakata K(corresponding author).
  • Journal Title: Cytoltine & Growth Factor Reviews. Volume: Vol.21 Issue.4 Pages: 263-273
  • Peer Reviewed
• [Journal Article] GM-CSF Autoantibodies Reproduce Pulmonary Alveolar Proteinosis in Non-human Primates. (2010)
  • Author(s): Sakagami T, (6人略)Nakata K, (5人略), Trapnell BC.
  • Journal Title: .Am J Respir Crit Care Med. Volume: 182(1) Pages: 49-46
  • Peer Reviewed
• [Journal Article] 稀少疾患をどう克服するか?-国際コンソーシアムの試み- (2010)
  • Author(s): 中田光、田澤立之
  • Journal Title: THE LUNG perspectivws 別冊 Volume: Vol.18 No.2 Pages: 129-132
  • Peer Reviewed
• [Journal Article] Pulmonary alveolar proteinosis associated with dust inhalation : not secondary but autoimmune? (2010)
  • Author(s): Costabel U, Nakata K.
  • Journal Title: Am J Respir Crit Care Med. Volume: 181(5) Pages: 427-428
  • Peer Reviewed
• [Journal Article] Inhaled Granuloqyちe1Macrophage-Colony Stimulating Factor as Therapy of Pulmonary Alveolar Proteinosis. (2010)
  • Author(s): Tazawa R, Ttapnell BC, (23人略), Nakata K(correaponding author).
  • Journal Title: Am J Respir Crit Care Med. Volume: 181(12) Pages: 1345-1354
  • Peer Reviewed
• [Journal Article] XI.肺胞蛋白症 GM-CSF製剤 (2010)
  • Author(s): 田澤立之、中田光
  • Journal Title: 日本内科学会雑誌 Volume: 99(7) Pages: 1623-1627
  • Peer Reviewed
• [Journal Article] 呼吸器疾患感受性-遺伝的背景-肺胞蛋白症 (2010)
  • Author(s): 田澤立之、中田光
  • Journal Title: 日本胸部臨床 Volume: 69(8) Pages: 735-740
  • Peer Reviewed
• [Journal Article] Aoell Epee assay to estimate theneutralizing capacity of granukeyte-macrophage colonystimulating factor autoantibodies. (2010)
  • Author(s): Urano S, (8人略)、Nakata K(tortesponding author).
  • Journal Title: J Immunol.Methods. Volume: 360(1-2) Pages: 141-148
  • Peer Reviewed
• [Journal Article] High avidity cytokine autoantibodies in health and disease : Pathogenesis and Mechanisms. (2010)
  • Author(s): Watanabe M, Uchida K, NakagakiK, TrapnellBC, Nakata K
  • Journal Title: Cytokine & Growth Factor Reviews (In press)
  • Peer Reviewed
• [Journal Article] Pulmonary alveolar proteinosis associated with dust inhalation : not secondary but autoimmune? (2010)
  • Author(s): Costabel U, Nakata K.
  • Journal Title: Am J Respir Crit Care Med 180 Pages: 427-428
  • Peer Reviewed
• [Journal Article] Comparative Study of High-Resolution CT Findings Between Autoimmune and Secondary Pulmonary Alveolar Proteinosis. (2009)
  • Author(s): Ishii H, Trapnell BC, Tazawa R, Inoue Y, Akira M, Kogure Y, Tomii K, Takada ; T, Hojo M, Ichiwata T, Goto H, Nakata K.
  • Journal Title: Chest. 136巻 Pages: 1348-1355
  • Peer Reviewed
• [Journal Article] Expression of Th2-skewed pathology mediators in monocyte-derived type 2 of dendritic cells (DC2). (2009)
  • Author(s): Hata M, Takahara S, Tsuzaki H, Ishii Y, Nakata K, Akagawa KS, Satoh K.
  • Journal Title: Immunol Lett. 126巻 Pages: 29-36
  • Peer Reviewed
• [Journal Article] Pulmonary alveolar proteinosis in a patient with Behcet's disease. (2009)
  • Author(s): Uchiyama M, Nagao T, Hattori A, Fujii T, Ichiwata T, Nakata K, Tani K, Hayashi T.
  • Journal Title: Respirology. 14巻 Pages: 305-308
  • Peer Reviewed
• [Journal Article] Comparative Study of High-Resolution CT Findings Between Autoimmune and Secondary Pulmonary Alveolar Proteinosis (2009)
  • Author(s): Ishii H, Trapnell BC, Tazawa R, Inoue Y, Akira M, Kogure Y, Tomii K, Takada ; T, Hojo M, Ichiwata T, Goto H, Nakata K
  • Journal Title: Chest 136 Pages: 1348-1355
  • Peer Reviewed
• [Journal Article] Expression of Th2-skewed pathology mediators in monocyte-derived type 2 of dendritic cells (DC2) (2009)
  • Author(s): Hata M, Takahara S, Tsuzaki H, Ishii Y, Nakata K, Akagawa KS, Satoh K.
  • Journal Title: Immunol Lett. 126 Pages: 29-36
  • Peer Reviewed
• [Journal Article] Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. http://www.ncbi.nlm.nih.gov/pubmed/19282464?log$=activity (2009)
  • Author(s): Uchida K, Nakata K, Suzuki T, Luisetti M, Watanabe M, Koch DE, Stevens CA, Beck DC, Denson LA, Carey BC, Keicho N, Krischer JR Yamada Y, Trapnell BC.
  • Journal Title: BLOOD 113 Pages: 2547-2556
  • Peer Reviewed
• [Journal Article] Pulmonary alveolar proteinosis in a patient with Behcet's disease. (2009)
  • Author(s): Uchiyama M, Nagao T, Hattori A, Fujii T, lchiwata T, Nakata K, Tani K, Hayashi T.
  • Journal Title: Respirology. 14 Pages: 305-308
  • Peer Reviewed
• [Journal Article] Granulocyte/macrophage-colony-stimulating factor autoantibodies and myeloid cell immune functions in healthy subjects. (2008)
  • Author(s): Uchida K, Nakata K, Suzuki T, Luisetti M, Watanabe M, Koch DE, Stevens CA, Beck DC, Denson LA, Carey BC, Keicho N, Krischer JP, Yamada Y, Trapnell BC.
  • Journal Title: Blood. 113巻 Pages: 2547-2556
  • Peer Reviewed
• [Journal Article] A combination therapy of whole lung lavage and GM-CSF inhalation in pulmonary alveolar proteinosis. (2008)
  • Author(s): Yamamoto H, Yamaguchi E, Agata H, Kandatsu N, Komatsu T, Kawai S, Baba K, Awaya T, Nishikomori R, Tsurusawa M, Nakata K.
  • Journal Title: Pediatric Pneumocology 43巻 Pages: 828-830
  • Peer Reviewed
• [Journal Article] A combination therapy of whole lung lavage and GM-CSF inhalation in pulmonary alveolar proteinosis. (2008)
  • Author(s): Yamamoto H, Yamaguchi E, Agata H, Kandatsu N, Komatsu T, Kawai s, Baba K, Awaya T, Nishikomori R, Tsurusawa M, Nakata K
  • Journal Title: Pediatric Pneumocology 43 Pages: 828-830
  • Peer Reviewed
• [Journal Article] XI.肺胞蛋白症GM-CSF製剤
  • Author(s): 田澤立之、中田光
  • Journal Title: 日本内科学会雑誌 99(7)巻 Pages: 1623-1627
  • Peer Reviewed
• [Presentation] Pulmonary alveolar proteinsosis : Historical Perspective. (2011)
  • Author(s): 中田光
  • Organizer: 3rd International Congress. Progress in Respiratory Medicine.
  • Place of Presentation: Cascina Scova(Italy)
  • Year and Date: 2011-03-31
• [Presentation] Pulmonary alveolar proteinsosis : Historical Perspective. (2011)
  • Author(s): Koh Nakata
  • Organizer: 3rd International Congress. Progress in Respiratory Medicine.
  • Place of Presentation: Cascina Scova (Pavia)
  • Year and Date: 2011-03-31
• [Presentation] 肺胞蛋白症:発症メカニズムとGM-CSF吸入療法 (2010)
  • Author(s): 中田光
  • Organizer: ヒューマンサイエンス総合研究セミナー
  • Place of Presentation: 全社協・灘尾ホール(東京都)
  • Year and Date: 2010-11-17
• [Presentation] 肺胞マクロファージが教えてくれた呼吸器病研究のおもしろさ・すばらしさ (2010)
  • Author(s): 中田光
  • Organizer: 第104回呼吸器疾患懇話会
  • Place of Presentation: 京葉銀行文化プラザ(千葉県)
  • Year and Date: 2010-10-27
• [Presentation] 肺胞マクロファージが教えてくれた呼吸器病研究のおもしろさ・すばらしさ (2010)
  • Author(s): 中田光
  • Organizer: 第104回呼吸器疾患懇話会
  • Place of Presentation: 京葉銀行文化プラザ(千葉東)
  • Year and Date: 2010-10-27
• [Presentation] 肺胞蛋白症では何故抗GM-CSF自己抗体が過剰に産生されるのか? (2010)
  • Author(s): 中田光
  • Organizer: 日本リンパ網内系学会
  • Place of Presentation: 朱鷺メッセ新潟コンベンションセンター(新潟県)
  • Year and Date: 2010-06-18
• [Presentation] 肺胞蛋白症では何故抗GM-CSF自己抗体が過剰に産生されるのか? (2010)
  • Author(s): 中田光
  • Organizer: 日本リンパ網内系学会
  • Place of Presentation: 朱鷺メッセ 新潟コンベンションセンター(新潟県)
  • Year and Date: 2010-06-18
• [Presentation] Mechanisms for Excessive Production of GM-CSF Autoantibody in Autoimmune Pulmonary Alveolar Proteinosis. (2010)
  • Author(s): Nei T, Urano S, Kaneko S, Motoi N, Takizawa J, Tazawa R, Nakagaki K, Akagawa K, Trapnell BC, Nakata K
  • Organizer: American Thoracic Society International Conference.
  • Place of Presentation: New Orleans Morial Convention Center(U.S.A.)
  • Year and Date: 2010-05-17
• [Presentation] GM-CSF AUTOANTIBODY; DISCOVERY, FUNCTIONS AND FUTUREAPPLICATIONS. (2010)
  • Author(s): Koh Nakata, Kanji Uchida.
  • Organizer: Meet the professor seminar.
  • Place of Presentation: New Orleans Morial Convention Center (LA)
  • Year and Date: 2010-05-17
• [Presentation] Mechanisms for Excessive Production of GM-CSF Autoantibody in Autoimmune Pulmonary Alveolar Proteinosis (2010)
  • Author(s): Nei T, Urano S, Kaneko C, Motoi N, Takizawa J, Tazawa R, Nakagaki K, Akagawa K, Trapnell BC, Nakata K
  • Organizer: American Thoracic Society
  • Place of Presentation: 米國/ニューオーリンズ
  • Year and Date: 2010-05-17
• [Presentation] 自己免疫性肺胞蛋白症における抗GM-CSF抗体産生機序 (2010)
  • Author(s): 根井貴仁、金子千夏、浦野真也、元井奈都紀、田澤立之、中田光
  • Organizer: 第50回日本呼吸器学会学術講演会
  • Place of Presentation: 国立京都国際会館(京都府)
  • Year and Date: 2010-04-24
• [Presentation] 自己免疫性肺胞蛋白症における抗GM-CSF抗体産生機序 (2010)
  • Author(s): 根井貴仁、金子千夏、浦野真也、元井奈都紀、田澤立之、中田光
  • Organizer: 第50回日本呼吸器学会学術講演会
  • Place of Presentation: 京都
  • Year and Date: 2010-04-24
• [Presentation] 厚生労働科学研究費補助金 難治性疾患克服研究事業 肺胞蛋白症の難治化要因の解明と診断、治療、管理の標準化と指針の確立に関する研究班 (2010)
  • Author(s): 根井貴仁、三須莉恵、金子千夏、浦野真也、元井奈都紀、田澤立之、中田光
  • Organizer: 第2回班会議
  • Place of Presentation: 千里ライフサイエンスセンタービル(大阪府)
  • Year and Date: 2010-01-09
• [Presentation] 自己免疫性肺胞蛋白症における抗GM-CSF抗体産生機序に関する研究 (2010)
  • Author(s): 根井貴仁、三須莉恵、金子千夏、浦野真也、元井奈都紀、田澤立之、中田光
  • Organizer: 厚生労働科学研究費補助金 難治性疾患克服研究事業 肺胞蛋白症の難治化要因の解明と診断、治療、管理の標準化と指針の確立に関する研究班 第2回班会議
  • Place of Presentation: 大阪
  • Year and Date: 2010-01-09
• [Presentation] TAND BLYMPHOCYTE SUBSETS ARE ACTIVATED IN THE PERIPHERAL BLOOD FROM PATIENTS WITH AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS., 2008 Tronto, Canada (2008)
  • Author(s): Nakata K, Kanazawa H, Nei T
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: カナダトロント
  • Year and Date: 2008-05-20
• [Presentation] T AND B LYMPHOCYTE SUBSETS ARE ACTIVATED IN THE PERIPHERAL BLOOD FROM PATIENTS WITH AUTOIMMUNE PULMONARY ALVEOLAR PROTEINOSIS. (2008)
  • Author(s): Nakata K, Kanazawa H, Nei T
  • Organizer: American Thoracic Society International Conference.
  • Place of Presentation: Metro Toronto Convention Center(Canada)
  • Year and Date: 2008-05-17
• [Book] 疾病と治療I (2010)
  • Author(s): 垣下榮三,(34人略)中田光,(72人略)吉矢和久
  • Total Pages: 366
  • Publisher: 南江堂
• [Book] ELSEVIER Textbook of Respiratory Medicine. (2010)
  • Author(s): Trapnell BC, Nakata K, Kavuru M.
  • Total Pages: 2400
• [Book] 病態のしくみがわかる免疫学 (2010)
  • Author(s): 安保徹,(18人略)中田光,(5人略)渡辺雅人
  • Total Pages: 296
  • Publisher: 医学書院
• [Book] 間質性肺疾患診療マニュアル (2010)
  • Author(s): 藤田次郎, 久保恵嗣,(69人略)中田光,(3人略)岸本卓巳
  • Total Pages: 344
  • Publisher: 南江堂
• [Book] 疾病と治療1 (2010)
  • Author(s): 垣下榮三, (34人略)中田光, (72人略)吉矢和久
  • Total Pages: 366
  • Publisher: 南江堂
• [Book] 7bxtbook of Respiratory Medicine. (2010)
  • Author(s): Trapnell BC, Nakata K, KavuruM, Pulmonary.
  • Total Pages: 2400
  • Publisher: ELSEVIER
• [Book] 病態のしくみがわかる免疫学 (2010)
  • Author(s): 安保徹, (18人略)中田光, (5人略)渡辺雅人
  • Total Pages: 296
  • Publisher: 医学書院
• [Book] 間質性肺疾患 診療マニュアル (2010)
  • Author(s): 藤田次郎, 久保恵嗣, (69人略)中田光, (3人略)岸本卓巳
  • Total Pages: 344
  • Publisher: 南江堂
• [Book] 新臨床内科学 第9版 (2008)
  • Author(s): 中田光, 他
  • Total Pages: 1920
  • Publisher: 医学書院
• [Book] 新臨床内科学 第9版 (2008)
  • Author(s): 中田 光
  • Publisher: 医学書院
• [Remarks] ホームページ等
  • URL: http://www.pap-guide.jp/index.html
• [Remarks]
  • URL: http://www.jove.com/index/Details.stp?ID=2742
• [Remarks]
  • URL: http://www.pap-guidejp/index.html
• [Remarks]
  • URL: http://www.jove.com/index/Details.stp?ID=2742
• [Patent(Industrial Property Rights)] 抗GM-CSF自己抗体及びその測定試薬 (2009)
  • Inventor(s): 中田光, 冨田正浩
  • Industrial Property Rights Holder: 新潟大学、ネオシルク
  • Industrial Property Number: 2009-119320
  • Filing Date: 2009-05-15
• [Patent(Industrial Property Rights)] 抗GM-CSF自己抗体及びその測定試薬 (2009)
  • Inventor(s): 中田光
  • Industrial Property Rights Holder: 中田光
  • Acquisition Date: 2009-09-11