ＣＡＲＤ１５の炎症性疾患における病態形成機序に関する研究

2014 Fiscal Year Annual Research Report

• Project/Area Number: 24591551
• Research Institution: Kyushu University
• Principal Investigator: 高田 英俊 九州大学, 医学(系)研究科(研究院), 教授 (70294931)
• Co-Investigator(Kenkyū-buntansha): 瀧本 智仁 九州大学, 大学病院, 助教 (50599511) ; 田中 珠美 九州大学, 医学(系)研究科(研究院), 研究員 (60423547)
• Project Period (FY): 2012-04-01 – 2015-03-31
• Keywords: 炎症性疾患 / 自己炎症 / Card15

Outline of Annual Research Achievements

新たにCARD15遺伝子異常による自己炎症性疾患を呈した患者のiPS細胞を患者末梢血単核球からセンダイウイルスを用いた方法により樹立した。同時に、家族性地中海熱、chronic infantile neurologic cutaneous and articular syndromeの患者由来末梢血からもiPS細胞を樹立し、OCT4、SOX2、TRA-1-81、TRA-1-60、NANOGなどの発現状態を確認し、マウスへの移植により多分化能を確認した。いずれの患者も該当する責任遺伝子の機能的な異常があることをるルシフェラーゼアッセイなどで確認している。iPS細胞からまずEmbryoid bodyを作成し、血液系細胞に分化させ、CD34、CD45、CD235a、の発現を検討し、血球系細胞への分化を確認した。さらにiPS細胞からCD11bを発現する細胞集団を同定した。Embryoid bodyからCD34陽性細胞をMACSで純化し、AGM-S3 stromal cell lineおよびSCF、IL-3、IL-6、TPO、G-CSFとともに12日間培養し、浮遊細胞をlow-adhesion plateで3日間培養した結果、好中球を含むmyeloid系細胞を分化させる事ができた。さらに、純化したCD34陽性細胞をgelatinでcoatしたdishに培養し、VE-Cadherinを発現する血管内皮細胞を分化誘導した。これらの細胞にさまざまな刺激を加え、培養上清や細胞のmRNA発現を検討を開始した。いくつかの細胞株で再現性のある結果を確認する必要があると考えている。

Research Products

• [Journal Article] Idiopathic disseminated bacillus Calmette–Guerin infection in three infants (2015)
  • Author(s): Kido J, Mizukami T, Ohara O, Takada H, Yanai M
  • Journal Title: Pediatrics International Volume: in press Pages: in press
  • Peer Reviewed
• [Journal Article] Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: a novel association with maternal uniparental isodisomy 6 (2015)
  • Author(s): Takimoto T, Takada H, Ishimura M, Kirino M, Hata K, Ohara O, Morio T, Hara T
  • Journal Title: Neonatology Volume: 107 Pages: 185-190
  • DOI: 10.1159/000370059
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Kawasaki disease-specific molecules in the sera are linked to microbe-associated molecular patterns in the biofilms (2014)
  • Author(s): Kusuda T, Nakashima Y, Murata K, Kanno S, Nishio H, Saito M, Tanaka T, Yamamura K, Sakai Y, Takada H, Miyamoto T, Mizuno Y, Ouchi K, Waki K, Hara T
  • Journal Title: PLoS One Volume: 20 Pages: e113054
  • DOI: 10.1371/journal.pone.0113054
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Two Novel Gain-of-Function Mutations of STAT1 Responsible for Chroni Mucocutaneous Candidiasis Disease: Impaired Production of IL-17A and IL-22, and the Presence of anti-IL-17F Autoantibody (2014)
  • Author(s): Yamazaki Y, Yamada M, Kawai T, Morio T, Onodera M, Ueki M, Watanabe N, Takada H, Takezaki S, Chida N, Kobayashi I, Ariga T
  • Journal Title: J Immunol Volume: 193 Pages: 4880-4887
  • DOI: 10.4049/jimmunol.1401467
  • Peer Reviewed
• [Journal Article] Successful treatment of non-Hodgkin's lymphoma using R-CHOP in a patient with Wiskott-Aldrich syndrome followed by a reduced-intensity stem cell transplant (2014)
  • Author(s): Koga Y, Takada H, Suminoe A, Ohga S, Hara T
  • Journal Title: Pediatr Transplant Volume: 18 Pages: E208-11
  • DOI: 10.1111/petr.12297
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Early progression of atherosclerosis in children with chronic infantile neurological cutaneous and articular syndrome (2014)
  • Author(s): Yamamura K, Takada H, Uike K, Nakashima Y, Hirata Y, Nagata H, Takimoto T, Ishimura M, Morihana E, Ohga S, Hara T
  • Journal Title: Rheumatology Volume: 53 Pages: 1783-1787
  • DOI: 10.1093/rheumatology/keu180
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Efficacy and safety of IgPro20, a subcutaneous immunoglobulin, in Japanese patients with primary immunodeficiency diseases (2014)
  • Author(s): Kanegane H, Imai K, Yamada M, Takada H, Ariga T, Bexon M, Rojavin M, Hu W, Kobayashi M, Lawo JP, Nonoyama S, Hara T, Miyawaki T
  • Journal Title: J Clin Immunol Volume: 34 Pages: 204-211
  • DOI: 10.1007/s10875-013-9985-z
  • Peer Reviewed / Acknowledgement Compliant
• [Presentation] Wiskott-Aldrich syndrome in a girl caused by heterozygous WASP mutation and extremely skewed X-chromosome inactivation: an association of non-random X-chromosome inactivation and uniparental isodisomy 6 (2014)
  • Author(s): Takada H, Takimoto T, Ishimura M, Urata M, Morio T, Hara T
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Mutations in Bruton’s tyrosine kinase impair IgA responses (2014)
  • Author(s): Mitsuiki N, Yang X, Bartol S, Kosaka Y, Takada H, Imai K, Kanegane H, Mizutani S, Burg VD, Zeim MV, Ohara O, Morio T
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Association between primary immunodeficiency diseases and vasculitis syndrome (2014)
  • Author(s): Hara T, Ishimura M, Takada H, Kusuda Y, Nakashima Y, Murata K, Kanno S, Nishio H
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Presentation] Safety and tolerability of Hizentra in patients with primary immunodeficiency in Japan, Europe, and the US (2014)
  • Author(s): Kanegane H, Imai K, Yamada M, Takada H, Ariga T, Hara T, Rojavin M, Hu W, Hubsch A, Nonoyama S
  • Organizer: 16th Biennial Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Prague, Czech Repubic
  • Year and Date: 2014-10-29 – 2014-11-01
• [Book] 小児の臓器移植および免疫不全状態における予防接種ガイドライン2014 (2014)
  • Author(s): 高田英俊
  • Total Pages: 127
  • Publisher: 協和企画