Establishment and elucidation of a mathematical model that explains the pathogenesis of pulmonary alveolar proteinosis.

• Project/Area Number: 15K15321
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Niigata University
• Principal Investigator: NAKATA Koh 新潟大学, 医歯学総合病院, 教授 (80207802)
• Co-Investigator(Kenkyū-buntansha): 田澤 立之 新潟大学, 医歯学総合病院, 准教授 (70301041) ; 北村 信隆 新潟大学, 医歯学総合病院, 特任教授 (90224972) ; 井上 義一 独立行政法人国立病院機構(近畿中央胸部疾患センター臨床研究センター), 臨床研究センター, 臨床研究センター長 (90240895)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2017: ¥780,000 (Direct Cost: ¥600,000、Indirect Cost: ¥180,000); Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
• Keywords: 自己免疫性肺胞蛋白症 / 抗GM-CSF自己抗体 / 内因性GM-CSF / 免疫複合体 / 全肺洗浄法 / 肺胞蛋白症 / 分子細胞呼吸器学

Outline of Final Research Achievements

During whole lung lavage, the concentration of GM-CSF autoantibody in the lavage fluid decreased serially to 0.1% of the first lavage fluid, whereas GM-CSF production by alveolar type II cells remained and form immune complex with GM-CSF autoantibody entered into the alveoli from the blood. The complex may be gradually absorbed by macrophages. These reactions can be expressed as a mathematical equations. Here, we noticed that the initial conditions such as GM-CSF production level and number of GM-CSF autoantibody molecules affect the simulation by the equations.

Research Products

• [Journal Article] Peripheral alveolar nitric oxide concentration reflects alveolar inflammation in autoimmune pulmonary alveolar proteinosis. (2018)
  • Author(s): Hirano T, Ohkouchi S, Tode N, Kobayashi M, Ono M, Satoh T, Mitsuishi Y, Watanabe A, Tabata M, Irokawa T, Ogawa H, Sugiura H, Kikuchi T, Akasaka K, Tazawa R, Inoue Y, Nakata K, Kurosawa H, Ichinose M.
  • Journal Title: ERJ open research Volume: 4 Issue: 1 Pages: 00071-2017
  • DOI: 10.1183/23120541.00071-2017
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Heterozygous Mutations in OAS1 Cause Infantile-Onset Pulmonary Alveolar Proteinosis with Hypogammaglobulinemia. (2018)
  • Author(s): Cho K, Yamada M, Agematsu K, Kanegane H, Miyake N, Ueki M, Akimoto T, Kobayashi N, Ikemoto S, Tanino M, Fujita A, Hayasaka I, Miyamoto S, Tanaka-Kubota M, Nakata K, Shiina M, Ogata K, Minakami H, Matsumoto N, Ariga T.
  • Journal Title: Am J Hum Genet Volume: 102 Issue: 3 Pages: 480-486
  • DOI: 10.1016/j.ajhg.2018.01.019
  • NAID: 120006502505
  • Peer Reviewed / Open Access
• [Journal Article] Genetic basis for childhood interstitial lung disease among Japanese infants and children. (2018)
  • Author(s): Hayasaka I, Cho K, Akimoto T, Ikeda M, Uzuki Y, Yamada M, Nakata K, Furuta I, Ariga T, Minakami H.
  • Journal Title: Pediatr Res. Volume: 83(2) Issue: 2 Pages: 477-483
  • DOI: 10.1038/pr.2017.217
  • Peer Reviewed
• [Journal Article] A Semiquantitative Computed Tomographic Grading System for Evaluating Therapeutic Response in Pulmonary Alveolar Proteinosis (2017)
  • Author(s): Tokura Sayoko、Akira Masanori、Okuma Tomohisa、Tazawa Ryushi、Arai Toru、Sugimoto Chikatoshi、Matsumuro Akiko、Hirose Masaki et al.
  • Journal Title: Annals of the American Thoracic Society Volume: 14 Issue: 9 Pages: 1403-1411
  • DOI: 10.1513/annalsats.201607-574oc
  • Peer Reviewed
• [Journal Article] Sequential GM-CSF Inhalation after Whole Lung Lavage for Pulmonary Alveolar Proteinosis: A Report of Five Intractable Cases. (2017)
  • Author(s): Ohkouchi S, Akasaka K, Ichiwata T, Hisata S, Iijima H, Takada T, Tsukada H, Nakayama H, Machiya JI, Irokawa T, Ogawa H, Shibata Y, Ichinose M, Ebina M, Nukiwa T, Kurosawa H, Nakata K, Tazawa R
  • Journal Title: Ann Am Thorac Soc. Volume: 72 Issue: 8 Pages: 1074-1083
  • DOI: 10.1513/annalsats.201611-892bc
  • Peer Reviewed
• [Journal Article] Elderly-onset hereditary pulmonary alveolar proteinosis and its cytokine profile. (2017)
  • Author(s): Ito M, Nakagome K, Ohta H, Akasaka K, Uchida Y, Hashimoto A, Shiono A, Takada T, Nagata M, Tohyama J, Hagiwara K, Kanazawa M, Nakata K, Tazawa R.
  • Journal Title: BMC Pulmonary Medicine. Volume: 印刷中 Issue: 1 Pages: 40-40
  • DOI: 10.1186/s12890-017-0382-x
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Sequential GM-CSF inhalation after whole lung lavage for pulmonary alveolar proteinosis: a report of five intractable cases. (2017)
  • Author(s): Ohkouchi S, Akasaka K, Ichiwata T, Hisata S, Iijima H, Takada T, Tsukada H, Nakayama H, Machiya J, Irokawa T, Ogawa H, Shibata Y, Ichinose M, Ebina M, Nukiwa T, Kurosawa H, Nakata K, Tazawa R.
  • Journal Title: Annals of American Thoracic Society. Volume: 印刷中
  • Peer Reviewed / Open Access
• [Journal Article] Pulmonary alveolar proteinosis and granulocyte/macrophage-colony stimulating factor (GM-CSF) inhalation (2016)
  • Author(s): Tazawa R, Nakata K
  • Journal Title: Espert Opinion on Orphan Drugs Volume: 4 Issue: 1 Pages: 115-123
  • DOI: 10.1517/21678707.2016.1123150
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Two cases of autoimmune and secondary pulmonary alveolar proteinosis during immunosuppressive therapy in dermatomyositis with interstitial lung disease. (2016)
  • Author(s): Imura Y, Yukawa N, Handa T, Nakashima R, Murakami K, Yoshifuji H, Ohmura K, Ishii H, Nakata K, Mimori T.
  • Journal Title: Mod Rheumatol Volume: 11 Issue: 4 Pages: 1-6
  • DOI: 10.3109/14397595.2016.1153443
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Outcome of corticosteroid administration in autoimmune pulmonary alveolar proteinosis: a retrospective cohort study (2015)
  • Author(s): Keiichi Akasaka, Takahiro Tanaka, Nobutaka Kitamura, Shinya Ohkouchi, Ryushi Tazawa, Toshinori Takada, Toshio Ichiwata, Etsuro Yamaguchi, Masaki Hirose, Toru Arai, Kentaro Nakano, Takahito Nei, Haruyuki Ishii, Tomohiro Handa, Yoshikazu Inoue and Koh Nakata
  • Journal Title: BMC Pulmonary Medicine Volume: 15 Issue: 1 Pages: 88-88
  • DOI: 10.1186/s12890-015-0085-0
  • NAID: 120005758416
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Possible Involvement of Lung Cells Harboring an (2015)
  • Author(s): Moriyama M, Yano T, Furukawa T, Takada T, Ushiki T, Masuko M, Takizawa J, Sone H, Tazawa R, Saijo Y, Ishii H, Nakata K.
  • Journal Title: Ann Am Thorac Soc. Volume: 12 Pages: 1251-1253
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] 自己免疫性肺胞蛋白症のGM-CSF吸入療法 (2017)
  • Author(s): 田澤立之, 鈴木雅, 大河内眞也, 朝川勝也, 巽浩一郎, 泉信有, 石井晴之, 山口悦郎, 半田知宏, 井上義一, 富井啓介, 江田良輔, 森本浩之輔, 三上礼子, 田中崇裕, 上田隆宏, 北村信隆, 中田光.
  • Organizer: 第53回日本肺サーファクタント関連医学会
• [Presentation] The analysis of alveolar macrophage form in secondary pulmonary alveolar proteinosis complicated with myelodysplastic syndrome. (2017)
  • Author(s): Ishii H, Tazawa R, Ishida M, Saraya T, Inoue Y,Oda M, Nakata K.
  • Organizer: ERS2017
  • Int'l Joint Research
• [Presentation] Autoimmune pulmonary alveolar proteinosis complicated with infections: a nationwide surveillance study in Japan. (2017)
  • Author(s): Arai T,Kitaichi M,Akira M, Nakata K, Yamaguchi E, Setoguchi Y, Ichiwata T, Ebina M,Cho K,Tazawa R,Ishii H,Uchida1 K,Kida H, Sugimoto C, Matsumuro A, Hirose M, Imai Y, Kasai T,Inoue Y.
  • Organizer: ERS2017
  • Int'l Joint Research
• [Presentation] Comorbid interstitial lung diseases and collagen vascular diseases in pulmonary alveolar proteinosis: a nationwide surveillance in Japan. (2017)
  • Author(s): Inoue Y, Arai T, Akira M, Nakata K, Yamaguchi E,Setoguchi Y,Ichiwata T,Ebina M,Cho K,Tazawa R,Ishii H,Uchida K,Kida H, C Sugimoto, A Matsumuro, M Hirose, Y Imai, T Kasai, M Kitaichi.
  • Organizer: ERS2017
  • Int'l Joint Research
• [Presentation] 23.Cross-sectional and Longitudinal Measurement of Autoantibody Levels against GM-CSF is useful for predicting Clinical Courses of Autoimmune Pulmonary Alveolar Proteinosis. (2017)
  • Author(s): Yamaguchi E, Nishimura M, Takahashi A, Tanaka H, Yokoe N, Kosaka K, Yonezawa T, Kubo A.
  • Organizer: ERS2017
  • Int'l Joint Research
• [Presentation] Chronic Inhalation of Recombinant Human Granulocyte/Macrophage Colony Stimulating Factor (GM-CSF) and GM-CSF Antibody in Nonhuman Primates. (2017)
  • Author(s): Tazawa R, Nakagaki K, Ito Y, Iizuka M, Hashimoto A, Nakano R, Tanaka T, Akasaka K, Takeuchi S, Nakata K.
  • Organizer: ATS2017
  • Int'l Joint Research
• [Presentation] Change in Distribution of Pulmonary Blood During Whole Lung Lavage in Patients with Autoimmune Pulmonary Alveolar Proteinosis: A Simulation-Based Study (2017)
  • Author(s): Tsuyuzaki H, Uchida K, Tamai Y, Akasaka K, Ichiwata T, Nakata K, Inoue Y, Yamada Y.
  • Organizer: ATS2017
  • Int'l Joint Research
• [Presentation] Peripheral Alveolar Nitric Oxide Concentration Reflects Macrophage Inflammation of Auto-Immune Pulmonary Alveolar Proteinosis. (2017)
  • Author(s): Ohkouchi S, Hirano T, Sugiura H, Tabata M, Ogawa H, Kurosawa H, Inoue Y, Tazawa R, Nakata K, Ichinose M.
  • Organizer: ATS2017
  • Int'l Joint Research
• [Presentation] 顆粒球マクロファージコロニー刺激因子（GM‐CSF）慢性吸入動物での抗体中和能の推移 (2017)
  • Author(s): 田澤立之，中垣和英，伊藤祐子，橋本淳史，中野龍，田中崇裕，赤坂圭一，中田光．
  • Organizer: 第57回日本呼吸器学会学術講演会
• [Presentation] GM-CSF吸入療法:前臨床試験 (2016)
  • Author(s): 田澤 立之
  • Organizer: 第56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・京都市)
• [Presentation] カニクイザルでのGM-CSF反復吸入投与と抗体産生 (2016)
  • Author(s): 田澤 立之
  • Organizer: 第56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・京都市)
• [Presentation] 自己免疫性肺胞蛋白症患者の血清中抗GM-CSF自己抗体の変化と予後の関係 (2016)
  • Author(s): 松室昭子, 広瀬雅樹, 新井徹, 杉本親寿, 審良正則, 井上義一
  • Organizer: 第56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・京都市)
• [Presentation] Elderly-Onset Hereditary Pulmonary Alveolar Proteinosis and CSF2RA Mutation. (2016)
  • Author(s): Ito M,Nakagome K,Ohta H,Akasaka K,Uchida Y,Hashimoto A,Shiono A,Takada T,Nagata M,Tohyama J,Hagiwara K,Kanazawa M,Nakata K,Tazawa R
  • Organizer: American Thoracic Society International Conference2016
  • Place of Presentation: サンフランシスコ(アメリカ合衆国)
  • Int'l Joint Research
• [Presentation] Strategy for Development of New Drug against Intractable Rare Diseases (2016)
  • Author(s): 中田 光
  • Organizer: DIA日本年会
  • Place of Presentation: 東京ビッグサイト(東京都・江東区)
• [Presentation] Inhalation of Recombinant Human Granulocyte/Macrophage-Colony Stimulating Factor and Induction of the GM-CSF Antibody in Pulmonary Alveolar Proteinosis (2015)
  • Author(s): R. Tazawa, K. Nakagaki, Y. Ito, A. Hashimoto, T. Tanaka, K. Akasaka, K. Nakata
  • Organizer: American Thoracic Society International Conference
  • Place of Presentation: Colorado（U.S.A.）
  • Year and Date: 2015-05-16
  • Int'l Joint Research
• [Patent(Industrial Property Rights)] 酵母由来組換えヒトＧＭ－ＣＳＦに特異的に結合するモノクローナル抗体 (2016)
  • Inventor(s): 中田光、中垣和英、田澤立之
  • Industrial Property Rights Holder: 中田光、中垣和英、田澤立之
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: 2016-065437
  • Filing Date: 2016-03-29