New mouse model of rare lung disease and novel therapy with macrophages

• Project/Area Number: 16K21750
• Research Category: Fund for the Promotion of Joint International Research (Home-Returning Researcher Development Research)
• Allocation Type: Multi-year Fund
• Research Field: Respiratory organ internal medicine
• Research Institution: Jichi Medical University
• Principal Investigator: SUZUKI Takuji 自治医科大学, 医学部, 准教授 (80344670)
• Project Period (FY): 2017 – 2019
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥32,760,000 (Direct Cost: ¥25,200,000、Indirect Cost: ¥7,560,000)
• Keywords: 呼吸器疾患 / 肺胞蛋白症 / ノックアウトマウス / マクロファージ / iPS細胞

Outline of Final Research Achievements

Hereditary pulmonary alveolar proteinosis (hPAP) is rare genetic diseases caused by GM-CSF receptor alpha or beta gene (CSF2RA or CSF2RB, respectively) mutation. hPAP with CSF2RA gene mutation has been difficult to study due to the unavailability of a mouse model with Csf2ra gene mutation. We demonstrated the Csf2ra gene deficient mice are the faithful model of human hPAP with CSF2RA gene mutations. The characteristics of the Csf2ra gene deficient mice including lung histology, macrophage phenotype and function, bronchoalveolar lavage fluid appearance, gene expression profiles and PAP biomarkers showed similar abnormality as hPAP patients with CSF2RA gene mutations. We also demonstrated that pulmonary macrophage transplantation therapy is effective and safe in Csf2ra gene deficient mice. These results strongly support the potential utility of the new disease model mice and the feasibility of novel cell therapy for the patients with this specific genetic lung disease.

Academic Significance and Societal Importance of the Research Achievements

これまで存在しなかったヒトCSF2RA遺伝子変異による遺伝性肺胞蛋白症の有効な疾患モデルが確立されたことで、その病態解析および生物学的解析を行えるという学術的意義がある。また、新規治療法の開発といったトランスレーショナルな研究を行うことにより、患者さんへ治療法を還元していくという社会的意義がある。

Research Products

• [Int'l Joint Research] Cincinnati Children's Hospital Medical Center(アメリカ合衆国)
• [Int'l Joint Research] Hannover Medical Center(ドイツ)
• [Int'l Joint Research] Cincinnati Children's Hospital Medical Center（米国）
• [Int'l Joint Research] Hannover Medical Center（ドイツ）
• [Int'l Joint Research] Cincinnati Children's Hospital Medical Center(米国)
• [Int'l Joint Research] Hannover Medical Center(ドイツ)
• [Journal Article] Characteristics of 68 patients with clinically proven sarcoidosis based on the Japan Society of Sarcoidosis and Other Granulomatous Disorders 2015 criteria. (2020)
  • Author(s): Yamanouchi Y, Sawahata M, Sakamoto N, Hisata S, Shijubo N, Konno S, Yamaguchi T, Watanabe M, Kawashima H, Suzuki T, Bando M, Hagiwara K
  • Journal Title: Respir Investig. Volume: 58 Pages: 102-109
  • Peer Reviewed / Open Access
• [Journal Article] Increased Pulmonary GM-CSF Causes Alveolar Macrophage Accumulation. Mechanistic Implications for Desquamative Interstitial Pneumonitis (2020)
  • Author(s): Suzuki T, McCarthy C, Carey BC, Borchers M, Beck D, Wikenheiser- Brokamp KA, Black D, Chalk C, Trapnell BC
  • Journal Title: Am J Respir Cell Mol Biol. Volume: 62 Pages: 87-94
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Effective hematopoietic stem cell-based gene therapy in a murine model of hereditary pulmonary alveolar proteinosis. (2019)
  • Author(s): Hetzel M, Lopez-Rodriguez E, Mucci A, Nguyen AHH, Suzuki T, Shima K, Buchegger T, Dettmer S, Rodt T, Bankstahl JP, Malik P, Knudsen L, Schambach A, Hansen G, Trapnell BC, Lachmann N, Moritz T
  • Journal Title: Haematologica Volume: 105 Pages: 1147-1157
  • DOI: 10.3324/haematol.2018.214866
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Long-Term Safety and Efficacy of Gene-Pulmonary Macrophage Transplantation Therapy of PAP in Csf2ra-/-Mice. (2019)
  • Author(s): Arumugam P, Suzuki T, Shima K, McCarthy C, Sallese A, Wessendarp M, Ma Y, Meyer J, Black D, Chalk C, Carey B, Lachmann N, Moritz T, Trapnell BC
  • Journal Title: Mol Ther. Volume: 27 Pages: 1597-1611
  • DOI: 10.1016/j.ymthe.2019.06.010
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Interferon-β Improves Sepsis-related Alveolar Macrophage Dysfunction and Post-septic ARDS-related Mortality (2018)
  • Author(s): Hiruma T, Tsuyuzaki H, Uchida K, Trapnell BC, Yamamura Y, Kusakabe Y, Totsu T, Suzuki T, Morita S, Doi K, Noiri E, Nakamura K, Nakajima S, Yahagi N, Morimura N, Chang K, Yamada Y.
  • Journal Title: Am J Respir Cell Mol Biol. Volume: 印刷中 Pages: 45-55
  • DOI: 10.1165/rcmb.2017-0261oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Use of low-cost three-dimensional printer to simulate grasping of bronchial foreign body (2018)
  • Author(s): Nakayama M, Yamamoto S, Kaneko N, Mato N, Suzuki T, Hagiwara K.
  • Journal Title: Respirol Case Rep. Volume: 6
  • DOI: 10.1002/rcr2.351
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pulmonary Transplantation of Human Induced Pluripotent Stem Cell-derived Macrophages Ameliorates Pulmonary Alveolar Proteinosis. (2018)
  • Author(s): Happle C, Lachmann N, Ackermann M, Mirenska A, Göhring G, Thomay K, Mucci A, Hetzel M, Glomb T, Suzuki T, Chalk C, Glage S, Dittrich-Breiholz O, Trapnell B, Moritz T, Hansen G.
  • Journal Title: Am J Respir Crit Care Med. Volume: 198 Pages: 350-360
  • DOI: 10.1164/rccm.201708-1562oc
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Statin as a novel pharmacotherapy of pulmonary alveolar proteinosis. (2018)
  • Author(s): McCarthy C, Lee E, Bridges JP, Sallese A, Suzuki T, Woods JC, Bartholmai BJ, Wang T, Chalk C, Carey BC, Arumugam P, Shima K, Tarling EJ, Trapnell BC.
  • Journal Title: Nat Commun. Volume: 9 Pages: 3127-3127
  • DOI: 10.1038/s41467-018-05491-z
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] iPSC-Derived Macrophages Effectively Treat Pulmonary Alveolar Proteinosis in Csf2rb-Deficient Mice. (2018)
  • Author(s): Mucci A, Lopez-Rodriguez E, Hetzel M, Liu S, Suzuki T, Happle C, Ackermann M, Kempf H, Hillje R, Kunkiel J, Janosz E, Brennig S, Glage S, Bankstahl JP, Dettmer S, Rodt T, Gohring G, Trapnell B, Hansen G, Trapnell C, Knudsen L, Lachmann N, Moritz T.
  • Journal Title: Stem Cell Reports. Volume: 11 Pages: 696-710
  • DOI: 10.1016/j.stemcr.2018.07.006
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Targeting cholesterol homeostasis in lung diseases. (2017)
  • Author(s): Sallese A, Suzuki T, McCarthy C, Bridges J, Filuta A, Arumugam P, Shima K, Ma Y, Wessendarp M, Black D, Chalk C, Carey B, Trapnell BC.
  • Journal Title: Scientific Reports Volume: 7 Pages: 10211-10211
  • DOI: 10.1038/s41598-017-10879-w
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Inhibition of IRAK1 Ubiquitination Determines Glucocorticoid Sensitivity for TLR9-Induced Inflammation in Macrophages. (2017)
  • Author(s): Kong F, Liu Z, Jain VG, Shima K, Suzuki T, Muglia LJ, Starczynowski DT, Pasare C, Bhattacharyya S.
  • Journal Title: The Journal of Immunology Volume: 199 Pages: 3654-3667
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Function and Safety of Lentivirus-Mediated Gene Transfer for CSF2RA-Deficiency. (2017)
  • Author(s): Hetzel M**, Suzuki T**, Hashtchin AR, Arumugam P, Carey B, Schwabbauer M, Kuhn A, Meyer J, Schambach A, Van Der Loo J, Moritz T, Trapnell BC, Lachmann N. (** : These authors are equally contributed.)
  • Journal Title: Human Gene Therapy Methods Volume: 28 Pages: 318-329
  • DOI: 10.1089/hgtb.2017.092
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] CRISPR/Cas9 Genome Editing Therapy for Hereditary Pulmonary Alveolar Proteinosis. (2019)
  • Author(s): Shima K, Suzuki T, Ma Y, Mayhew C, Sallese A, Carey BC, Arumugam P, Trapnell BC
  • Organizer: American Thoracic Society 112th International Conference
  • Int'l Joint Research
• [Presentation] Long-Term Follow-Up of a Patient with GM-CSF Antibody-Negative Pulmonary Alveolar Proteinosis Following Exposure to Dust After the Great East Japan Earthquake. (2019)
  • Author(s): Hisata S, Suzuki T, Yamauchi H, Ohkouchi S, Bando M, Hagiwara K
  • Organizer: American Thoracic Society 112th International Conference
  • Int'l Joint Research
• [Presentation] Gene Editing for Pulmonary Alveolar Proteinosis. Technology & Research Workshop. Gene Editing (2018)
  • Author(s): Suzuki T.
  • Organizer: The 2018 International Rare Lung Disease Research Conference and LAMPOSIUM.
  • Int'l Joint Research / Invited
• [Presentation] Alveolar Macrophages and Lung Homeostasis. Symposium : Disease formation by macrophage dysfunction. (2018)
  • Author(s): Suzuki T.
  • Organizer: The 91^<st> Annual Meeting of the Japanese Biochemical Society.
  • Int'l Joint Research / Invited
• [Presentation] Pulmonary Macrophage Transplantation (PMT) Therapy of Hereditary Pulmonary Alveolar Proteinosis (hPAP) Is Effective with Mature Macrophages without Progenitor Expansion Requirement. (2017)
  • Author(s): Suzuki T, Arumugam P, Sallese T, Shima K, Trapnell B. C
  • Organizer: 日本呼吸器学会
• [Presentation] Development and Validation of Csf2ra Gene-Deficient Mice as a Clinically Relevant Model of Children with Hereditary Pulmonary Alveolar Proteinosis. (2017)
  • Author(s): Suzuki T, Shima K, Arumugam P, Ma Y, Black D, Chalk C, Carey B, Trapnell B. C
  • Organizer: American Thoracic Society 110th International Conference
  • Int'l Joint Research
• [Presentation] 遺伝性肺胞蛋白症に対する肺マクロファージ移植治療 (2017)
  • Author(s): 鈴木拓児、島賢治郎、Paritha Armugam、萩原弘一、Bruce Trapnell
  • Organizer: 第53回日本肺サーファクタント関連医学会
  • Invited
• [Presentation] Pulmonary Macrophage Transplantation Therapy in Csf2ra Gene-Deficient Mice, a Novel Clinically Relevant Model of Children with Hereditary Pulmonary Alveolar Proteinosis. (2017)
  • Author(s): Suzuki T, Shima K, Arumugam P, Trapnell B. C.
  • Organizer: The 5th Annual Meeting of the International Cytokine and Interferon Society
  • Int'l Joint Research