Elucidation of the pathophysiology of Langerhans cell histiocytosis by chemokine analysis

• Project/Area Number: 25461606
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Jichi Medical University
• Principal Investigator: Morimoto Akira 自治医科大学, 医学部, 教授 (30326227)
• Co-Investigator(Kenkyū-buntansha): 川原 勇太 自治医科大学, 医学部, 助教 (10570385) ; 塩田 曜子 国立研究開発法人国立成育医療研究センター, 小児がんセンター, 医師 (30307532) ; 早瀬 朋美 自治医科大学, 医学部, 助教 (50433587) ; 八木 正樹 自治医科大学, 医学部, 研究員 (60570398) ; 新島 瞳 (松本瞳 / 松本 瞳 / 新島 瞳(松本瞳)) 自治医科大学, 医学部, 助教 (70598937) ; 翁 由紀子 自治医科大学, 医学部, 助教 (30438650)
• Project Period (FY): 2013-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥5,070,000 (Direct Cost: ¥3,900,000、Indirect Cost: ¥1,170,000); Fiscal Year 2015: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: ランゲルハンス細胞組織球症 / ケモカイン / osteopontin / 破骨細胞様巨細胞 / 遺伝子多型 / サイトカイン / 多型性

Outline of Final Research Achievements

The serum levels of IL-9, IL-10, IL-15 and MIF in patients with Langerhans cell histiocytosis (LCH) were significantly high compared to those in Control. The serum levels of M-CSF and CCL 2 in patients with multisystem (MS) type LCH were significantly high compared to those in patients with single-system (SS) type LCH, while the serum levels of IL-18 and osteopontin (OPN) in patients with risk organ involvement (RO) positive MS type LCH were significantly high compared to those in patients with RO negative MS type LCH.
OPN was revealed to be essential for differentiation from immature dendritic cells to osteoclast-like giant cells.
In 48 LCH patients, OPN gene polymorphisms (rs9138, rs4754, rs11730582, rs1126772, rs1126616) were analyzed. No significant difference was identified in allele frequencies of these sites between LCH patients and controls, patients diagnosed under 2-years-old and over 2-years-old, patients with MS type and SS type, patients with MS-RO (+)and MS-RO (-).

Research Products

• [Journal Article] CNS-directed Prophylactic Approach to Langerhans Cell Histiocytosis. (2017)
  • Author(s): Imashuku S, Shioda Y, Morimoto A.
  • Journal Title: J Pediatr Hematol Oncol. Volume: 39 Issue: 4 Pages: 321-322
  • DOI: 10.1097/mph.0000000000000781
  • Peer Reviewed
• [Journal Article] Intensified and prolonged therapy comprising cytarabine, vincristine and prednisolone improves outcome in patients with multisystem Langerhans cell histiocytosis: results of the Japan Langerhans Cell Histiocytosis Study Group-02 Protocol Study. (2016)
  • Author(s): Morimoto A, Shioda Y, Imamura T, Kudo K, Kawaguchi H, Sakashita K, Yasui M, Koga Y, Kobayashi R, Ishii E, Fujimoto J, Horibe K, Bessho F, Tsunematsu Y, Imashuku S.
  • Journal Title: Int J Hematol. Volume: 104 Issue: 1 Pages: 99-109
  • DOI: 10.1007/s12185-016-1993-3
  • Peer Reviewed
• [Journal Article] Unique clonal relationship between T-cell acute lymphoblastic leukemia and subsequent Langerhans cell histiocytosis with TCR rearrangement and NOTCH1 mutation. (2015)
  • Author(s): Yokokawa Y, Taki T, Akiyama M, Kobayashi S, Nagoshi H, Chinen Y, Morimoto A, Ida H, Taniwaki M.
  • Journal Title: Genes Chromosomes Cancer Volume: 54 Issue: 7 Pages: 409-417
  • DOI: 10.1002/gcc.22252
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Acute-phase ITIH4 levels distinguish multi-system from single-system Langerhans cell histiocytosis via plasma peptidomics (2015)
  • Author(s): Murakami I, Oh Y, Morimoto A, Sano H, Kanzaki S, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Hayashi K, Imashuku S, Gogusev J, Jaubert F, Oka T, Yoshino T.
  • Journal Title: Clin Proteomics. Volume: 12 Issue: 1 Pages: 16-16
  • DOI: 10.1186/s12014-015-9089-2
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Follow-up of pediatric patients treated by IVIG for Langerhans cell histiocytosis (LCH)-related neurodegenerative CNS disease. (2015)
  • Author(s): Imashuku S, Fujita N, Shioda Y, Noma H, Seto S, Minato T, Sakashita K, Ito N, Kobayashi R, Morimoto A
  • Journal Title: Int J Hematol Volume: 101 Issue: 2 Pages: 191-197
  • DOI: 10.1007/s12185-014-1717-5
  • Peer Reviewed
• [Journal Article] Interleukin-1 loop model for pathogenesis of Langerhans cell histiocytosis (2015)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Nagata K, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Cell Commun Signal Volume: 13 Issue: 1 Pages: 13-13
  • DOI: 10.1186/s12964-015-0092-z
  • Peer Reviewed / Open Access
• [Journal Article] Merkel cell polyomavirus DNA sequences in peripheral blood and tissues from patients with Langerhans cell histiocytosis. (2014)
  • Author(s): Murakami I, Matsushita M, Iwasaki T, Kuwamoto S, Kato M, Horie Y, Hayashi K, Imamura T, Morimoto A, Imashuku S, Gogusev J, Jaubert F, Takata K, Oka T, Yoshino T.
  • Journal Title: Hum Pathol. Volume: 45 Issue: 1 Pages: 119-126
  • DOI: 10.1016/j.humpath.2013.05.028
  • Peer Reviewed
• [Journal Article] High serum osteopontin levels in pediatric patients with high risk Langerhans cell histiocytosis. (2014)
  • Author(s): Oh Y, Morimoto A, Shioda Y, Imamura T, Kudo K, Imashuku S
  • Journal Title: Cytokine Volume: 70 Issue: 2 Pages: 194-197
  • DOI: 10.1016/j.cyto.2014.07.002
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Osteopontin has a crucial role in osteoclast-like multinucleated giant cell formation (2014)
  • Author(s): Oh Yukiko, Oh Iekuni
  • Journal Title: Journal of cellular biochemistry Volume: 115 Issue: 3 Pages: 585-95
  • DOI: 10.1002/jcb.24695
  • Peer Reviewed / Open Access
• [Journal Article] Recent advances in Langerhans cell histiocytosis. (2014)
  • Author(s): Morimoto A, Oh Y, Shioda Y, Kudo K, Imamura T.
  • Journal Title: Pediatr Int Volume: 56 Issue: 4 Pages: 451-461
  • DOI: 10.1111/ped.12380
  • Peer Reviewed