Establishing the research basis for innovative medical care of familial hemophagocytic lymphohistiocytosis.

• Project/Area Number: 25670475
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Pediatrics
• Research Institution: Kyoto University
• Principal Investigator: HEIKE Toshio 京都大学, 医学(系)研究科(研究院), 教授 (90190173)
• Co-Investigator(Kenkyū-buntansha): YASUMI Takahiro 京都大学, 大学院医学研究科発達小児科学, 講師 (00511891)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000); Fiscal Year 2015: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2014: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2013: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 血球貪食性リンパ組織球症 / 免疫調節異常症 / 機能解析 / 創薬基盤開発 / FHL / 血球貪食症候群 / NK細胞 / 細胞障害性T細胞

Outline of Final Research Achievements

We established a system to provide comprehensive screening of FHL to all HLH patients by the detection of perforin expression in NK cells; Munc13-4, syntaxin-11, and Munc18-2 expression in platelets; by NK cell and CTL degranulation assays; and by genetic analysis. We compared the levels of serum sIL2R, ferritin, and other readily available laboratory parameters among pediatric HLH patients during the early stage of the disease, and showed that these parameters can be used to predict the underlying etiology and to efficiently identify patients who need molecular screening for FHL.（Yasumi, et al. British J Haematology, 2015）
We also established a system to analyze the cytolytic activity and the degranulation capacity of CTL lines derived from HLH patients. In addition, we have succeeded in evaluating the effect of a UNC13D mutation by transfecting the mutated cDNA construct into CTL lines established from a FHL3 patient.

Research Products

• [Journal Article] Laboratory parameters identify familial haemophagocytic lymphohistiocytosis from other forms of paediatric haemophagocytosis (2015)
  • Author(s): Yasumi T, Hori M, Hiejima E, Shibata H, Izawa K, Oda H, Yoshioka K, Nakagawa K, Kawai T, Nishikomori R, Ohara O, Heike T
  • Journal Title: British Journal of Haematology Volume: 170 Issue: 4 Pages: 532-538
  • DOI: 10.1111/bjh.13461
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Heterogeneity of HLH pathophysiology and treatment strategies (2015)
  • Author(s): 八角高裕、柴田洋史、下寺佐栄子、平家俊男
  • Journal Title: Rinsho Ketsueki Volume: 56 Issue: 10 Pages: 2248-2257
  • DOI: 10.11406/rinketsu.56.2248
  • NAID: 130005103313
  • ISSN: 0485-1439, 1882-0824
• [Presentation] HLH病態の多様性と治療戦略の展望 (2015)
  • Author(s): 八角高裕
  • Organizer: 第77回日本血液学会
  • Place of Presentation: ANAクラウンプラザホテル金沢
  • Year and Date: 2015-10-18
  • Invited
• [Presentation] CD57+ CTL degranulation and Munc13-4 protein expression assays are sensitive and reliable screening methods for FHL3 (2015)
  • Author(s): Kikuya A, Hori M, Yasumi T, Hiejima E, Shibata H, Izawa K, Oda H, Nishikomori R, Ohara O, Heike T
  • Organizer: 第11回アジア小児研究学会
  • Place of Presentation: 大阪国際会議場
  • Year and Date: 2015-04-15
  • Int'l Joint Research
• [Presentation] 当科におけるFHL（家族性血球貪食性リンパ組織球症）スクリーニングの現状 (2014)
  • Author(s): 堀雅之
  • Organizer: 第117回日本小児科学会学術集会
  • Place of Presentation: 名古屋国際会議場
  • Year and Date: 2014-04-13