Control of amyloid neuropathy from the aspect of inflammation

2016 Fiscal Year Annual Research Report

• Project/Area Number: 15K15195
• Research Institution: Kumamoto University
• Principal Investigator: 安東 由喜雄 熊本大学, 大学院生命科学研究部(医), 教授 (20253742)
• Co-Investigator(Kenkyū-buntansha): 田崎 雅義 熊本大学, 大学院生命科学研究部(保), 助教 (50613402) ; 植田 光晴 熊本大学, 医学部附属病院, 講師 (60452885) ; 三隅 洋平 熊本大学, 大学院生命科学研究部(医), 助教 (80625781) ; 山下 太郎 熊本大学, 医学部附属病院, 特任教授 (90381003) ; 大林 光念 熊本大学, 大学院生命科学研究部(保), 教授 (90361899)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Keywords: 臨床化学

Outline of Annual Research Achievements

これまでの研究から以下の事が判明した。
1.血清中の炎症性サイトカイン濃度の比較検討：FAP患者、健常各20名の血清中に含まれるIL-1β,IL-6,IL-12 といった炎症性サイトカインの濃度をELISA法により測定、比較検討したところIL-6がFAP患者で上昇していた。
2.患者組織アミロイドでの補体の検索：患者の組織検体を用いてアミロイド中での補体の共存を検討したところ、アミロイド中に高率にC5aが共存していた。
3.FAPモデルマウスに対する補体阻害剤の効果：上記の解析結果で病態との関連が強い補体に対する阻害剤をモデルマウスに投与し、病理学的な変化や表現型に及ぼす影響を検証してみたが有意な変化は検出できなかった。
4.末梢血単核球のフェノタイプ解析：FAP患者、健常者から採血を行い、Ficollによる PBMCの分離後、フローサイトメトリーによる解析を行う。発現を調べるマーカーとして、CD4,CD8,CD19,CD14に対する抗体を用いてT細胞、B細胞、単球などの一般的な免疫細胞の割合を算出した。更に、これらのマーカーと組み合わせて、CD16,CD163,CD206,IFN-γ, IL-4,IL-17,Foxp3等のマーカーの検出も行ったところ、炎症性の単球や炎症性のT細胞の上昇傾向が認められた。
総合的にFAP患者では、「 micro inflammation 」がおこっており、それを制御する事が治療につながると判明した。

Research Products

• [Journal Article] A clinical evaluation of renal amyloidosis in the Japan renal biopsy registry: a cross-sectional study. (2017)
  • Author(s): Nishi S, Muso E, Shimizu A, Sugiyama H, Yokoyama H, Ando Y, Goto S, Fujii H
  • Journal Title: Clin Exp Nephrol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1007/s10157-016-1326-0
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Clinicopathological and biochemical findings of thyroid amyloid in hereditary transthyretin amyloidosis with and without liver transplantation. (2017)
  • Author(s): Huang G, Ueda M, Tasaki M, Yamashita T, Misumi Y, Masuda T, Suenaga G, Inoue Y, Kinoshita Y, Matsumoto S, Mizukami M, Tsuda Y, Nomura T, Obayashi K, Ando Y
  • Journal Title: Amyloid Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1080/13506129.2016.1276440.
  • Peer Reviewed
• [Journal Article] Light chain deposition disease diagnosed with laser micro-dissection, liquid chromatography, and tandem mass spectrometry of nodular glomerular lesions. (2017)
  • Author(s): Kasagi T, Nobata H, Suzuki K, Miura N, Banno S, Takami A, Yamashita T, Ando Y, Imai H
  • Journal Title: Intern Med Volume: 56 Pages: 61-66
  • DOI: 10.2169/internalmedicine.56.7275.
  • Peer Reviewed / Open Access
• [Journal Article] Novel screening for transthyretin amyloidosis by using fat ultrasonography. (2017)
  • Author(s): Misumi Y, Ueda M, Yamashita T, Masuda T, Kinoshita Y, Tasaki M, Nagase T, Ando Y
  • Journal Title: Ann Neurol Volume: 印刷中 Pages: 印刷中
  • DOI: 10.1002/ana.24914.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Rapid detection of wild-type and mutated transthyretins. (2016)
  • Author(s): Tasaki M, Ueda M, Obayashi K, Motokawa H, Kinoshita Y, Suenaga G, Yanagisawa A, Toyoshima R, Misumi Y, Masuda T, Yamashita T, Ando Y
  • Journal Title: Ann Clin Biochem Volume: 53 Pages: 508-510
  • DOI: 10.1177/0004563215605541.
  • Peer Reviewed
• [Journal Article] Recipient aging accelerates acquired transthyretin amyloidosis after domino liver transplantation. (2016)
  • Author(s): Misumi Y, Narita Y, Oshima T, Ueda M, Yamashita T, Tasaki M, Obayashi K, Isono K, Inomata Y, Ando Y
  • Journal Title: Liver Transpl Volume: 22 Pages: 656-664
  • DOI: 10.1002/lt.24371.
  • Peer Reviewed / Open Access
• [Journal Article] Knee osteoarthritis associated with different kinds of amyloid deposits and the impact of aging on type of amyloid. (2016)
  • Author(s): Yanagisawa A, Ueda M, Sueyoshi T, Nakamura E, Tasaki M, Suenaga G, Motokawa H, Toyoshima R, Kinoshita Y, Misumi Y, Yamashita T, Sakaguchi M, Westermark P, Mizuta H, Ando Y
  • Journal Title: Amyloid Volume: 23 Pages: 26-32
  • DOI: 10.3109/13506129.2015.1115758.
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Labial salivary gland biopsy for diagnosing immunoglobulin light chain amyloidosis: a retrospective analysis. (2016)
  • Author(s): Suzuki T, Kusumoto S, Yamashita T, Masuda A, Kinoshita S, Yoshida T, Takami-Mori F, Takino H, Ito A, Ri M, Ishida T, Komatsu H, Ueda M, Ando Y, Inagaki H, Iida S
  • Journal Title: Ann Hematol Volume: 95 Pages: 279-285
  • DOI: 10.1007/s00277-015-2549-y.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Long-term outcome of patients with hereditary transthyretin V30M amyloidosis with polyneuropathy after liver transplantation. (2016)
  • Author(s): Okumura K, Yamashita T, Masuda T, Misumi Y, Ueda A, Ueda M, Obayashi K, Jono H, Yamashita S, Inomata Y, Ando Y
  • Journal Title: Amyloid Volume: 13 Pages: 1-7
  • DOI: 10.3109/13506129.2015.1123149.
  • Peer Reviewed
• [Journal Article] Phase 1 study of bortezomib in combination with melphalan and dexamethasone in Japanese patients with relapsed AL amyloidosis. (2016)
  • Author(s): Shimazaki C, Fuchida S, Suzuki K, Ishida T, Imai H, Sawamura M, Takamatsu H, Abe M, Miyamoto T, Hata H, Yamada M, Ando Y
  • Journal Title: Int J Hematol Volume: 103 Pages: 79-85
  • DOI: 10.1007/s12185-015-1901-2.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Effects of tafamidis treatment on transthyretin(TTR) stabilization, efficacy, and safety in Japanese patients with familial amyoid polyneuropathy(TTR-FAP) with Val30Met and non-Varl30Met:A phase III, open-label study. (2016)
  • Author(s): Ando Y, Sekijima Y, Obayashi K, Yamashita T, Ueda M, Misumi Y, Morita H, Machii K, Ohta M, Takata A, Ikeda S
  • Journal Title: J Neurol Sci Volume: 15 Pages: 266-271
  • DOI: 10.1016/j.jns.2016.01.046.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Transthyretin-related familial amyloidotic polyneuropathy found with abnormal urinalysis at a general health checkup. (2016)
  • Author(s): Yoshimura Y, Kuwabara T, Shiraishi N, Kakizoe Y, Tasaki M, Obayashi K, Ando Y, Mukoyama M
  • Journal Title: Nephrology (Carlton) Volume: 21 Pages: 341-342
  • DOI: 10.1111/nep.12610.
  • Peer Reviewed / Open Access
• [Journal Article] Endoscopic findings of small-bowel lesions in familial amyloid polyneuropathy: A case report. (2016)
  • Author(s): Asakura K, Yanai S, Nakamura S, Kawaski1 K, Eizuka M, Ishida K, Sugai T, Ueda M, Yamashita T, Ando Y, Matsumoto T
  • Journal Title: Medicine (Baltimore) Volume: 95 Pages: e2896
  • DOI: 10.1097/MD.0000000000002896.
  • Peer Reviewed / Open Access
• [Journal Article] Sources of variation of transthyretin in healthy subjects in east and southeast asia: Clinical and experimental evidence for the effect of alcohol on transthyretin metabolism. (2016)
  • Author(s): Jono H, Su Y, Obayashi K, Tanaka Y, Ishiguro A, Nishimura H, Shinriki S, Ueda M, Ikeda K, Yamagata K, Ichihara K, Ando Y, Scientific Committee for the Asia-Pacific Federation of Clinical Biochemistry
  • Journal Title: Clin Chim Acta Volume: 458 Pages: 5-11
  • DOI: 10.1016/j.cca.2016.04.011.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Hereditary amyloidosis with cardiomyopathy caused by the novel variant transthyretin A36D. (2016)
  • Author(s): Yamashita T, Ueda M, Saga N, Nanto K, Tasaki M, Masuda T, Misumi Y, Oda S, Fujimoto A, Amano T, Takamatsu K, Yamashita S, Obayashi K, Matsui H, Ando Y
  • Journal Title: Amyloid Volume: 23 Pages: 207-208
  • DOI: 10.1080/13506129.2016.1202228
  • Peer Reviewed
• [Journal Article] Involvement of macrophages in the pathogenesis of familial amyloid polyneuropathy and efficacy of human iPS cell-derived macrophages in its treatment. (2016)
  • Author(s): Suenaga G, Ikeda T, Komohara Y, Takamatsu K, Kakuma T, Tasaki M, Misumi Y, Ueda M, Ito T, Senju S, Ando Y
  • Journal Title: PLoS One Volume: 11 Pages: e0163944
  • DOI: 10.1371/journal.pone.0163944.
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Novel antibody for the treatment of transthyretin amyloidosis. (2016)
  • Author(s): Hosoi A, Su Y, Torikai M, Jono H, Ishikawa D, Soejima K, Higuchi H, Guo J, Ueda M, Suenaga G, Motokawa H, Ikeda T, Senju S, Nakashima T, Ando Y
  • Journal Title: J Biol Chem Volume: 25 Pages: 25096-25105
  • DOI: 10.1074/jbc.M116.738138
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Schwann cell and endothelial cell damage in transthyretin familial amyloid polyneuropathy. (2016)
  • Author(s): Koike H, Ikeda S, Takahashi M, Kawagashira Y, Iijima M, Misumi Y, Ando Y, Ikeda SI, Katsuno M, Sobue G
  • Journal Title: Neurology Volume: 87 Pages: 2220-2229
  • DOI: 10.1212/WNL.0000000000003362
  • Peer Reviewed
• [Journal Article] Influence of heparin molecular size on the induction of C- terminal unfolding in β2-microglobulin. (2016)
  • Author(s): Fukasawa K, Higashimoto Y, Motomiya Y, Uji Y, Ando Y
  • Journal Title: Mol Biol Res Commun Volume: 5 Pages: 225-232
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Amyloidosis Medical Practice Center in Japan by Kumamoto University. (2017)
  • Author(s): Yamashita T, Ueda M, Tasaki M, Masuda1 T, Misumi M, Takamatsu K, Obayashi K, Ando Y
  • Organizer: VI Advance and Research in TTR Amyloidosis
  • Place of Presentation: Vienna, Austria
  • Year and Date: 2017-02-24 – 2017-02-25
  • Int'l Joint Research / Invited
• [Presentation] 臨床化学を通して我々は何をやってきたのか (2016)
  • Author(s): 安東由喜雄
  • Organizer: 第５６回日本臨床化学会
  • Place of Presentation: 熊本
  • Year and Date: 2016-12-02 – 2016-12-04
  • Invited
• [Presentation] C末端側トランスサイレチンのアミロイド形成における生化学的解析 (2016)
  • Author(s): 植田光晴、水口峰之、三隅洋平、増田曜章、津田幸元、田崎雅義、松本紗也加、水上真由美、末永元輝、井上泰輝、木下祐美子、野村隼也、山下太郎、大林光念、安東由喜雄
  • Organizer: 第56回日本臨床化学会 年次学術集会
  • Place of Presentation: 熊本
  • Year and Date: 2016-12-02 – 2016-12-04
• [Presentation] 家族性アミロイドポリニューロパチーと自律神経障害 (2016)
  • Author(s): 安東由喜雄
  • Organizer: 第５９回日本自律神経学会
  • Place of Presentation: 熊本
  • Year and Date: 2016-11-10 – 2016-11-11
  • Invited
• [Presentation] 家族性アミロイドポリニューロパチーにおけるアミロイド形成過程の解析 (2016)
  • Author(s): 植田光晴、水口峰之、三隅洋平、増田曜章、津田幸元、田崎雅義、松本紗也加、水上真由美、末永元輝、井上泰輝、木下祐美子、野村隼也、山下太郎、大林光念、安東由喜雄
  • Organizer: 第69回日本自律神経学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2016-11-10 – 2016-11-11
• [Presentation] 同一コドン内の二塩基置換による遺伝性トランスサイレチンアミロイドーシスATTR Val28Serの臨床像解析 (2016)
  • Author(s): 三隅洋平、岡田匡充、植田光晴、山下太郎、増田曜章、田崎雅義、安東由喜雄
  • Organizer: 第69回日本自律神経学会総会
  • Place of Presentation: 熊本
  • Year and Date: 2016-11-10 – 2016-11-11
• [Presentation] トランスサイレチンアミロイドーシス診断のポイントと治療最前線 (2016)
  • Author(s): 植田光晴、安東由喜雄
  • Organizer: 第20回日本心不全学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2016-10-08
• [Presentation] アミロイドアンギオパチーの最新の知見 (2016)
  • Author(s): 安東由喜雄
  • Organizer: 第１３回早期認知症学会
  • Place of Presentation: 熊本
  • Year and Date: 2016-09-17 – 2016-09-18
  • Invited
• [Presentation] Hereditary transthyretin Y114C-related cerebral amyloid angiopathy (2016)
  • Author(s): Yamashita T, Ando Y
  • Organizer: 4th Annual Meeting of the Japan Amyloidosis Research Society, Special Symposium: Central Nervous System Involvement in the Patients with ATTR Amyloidosis
  • Place of Presentation: Tokyo
  • Year and Date: 2016-08-19
  • Int'l Joint Research / Invited
• [Presentation] 同一コドン内の二塩基置換による新規遺伝性トランスサイレチンアミドーシスATTR Val28Ser (p.Val48Ser)の一症例 (2016)
  • Author(s): 三隅洋平、岡田匡充、植田光晴、山下太郎、増田曜章、田崎雅義、安東由喜雄
  • Organizer: 第4回日本アミロイドーシス研究会学術集会
  • Place of Presentation: 東京
  • Year and Date: 2016-08-19
• [Presentation] アミロイドアンギオパチーの病態と治療の展望．シンポジウム「アミロイドーシスと腎：診断と治療の進歩」 (2016)
  • Author(s): 植田光晴、井上泰輝、山下太郎、安東由喜雄
  • Organizer: 第59回日本腎臓学会学術集会
  • Place of Presentation: 横浜
  • Year and Date: 2016-07-17 – 2016-07-19
• [Presentation] Antibody therapy for familial amyloid polyneuropathy (2016)
  • Author(s): Ando Y
  • Organizer: XVth International Symposium on amyloidosis, Uppsala
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03 – 2016-07-07
  • Int'l Joint Research / Invited
• [Presentation] Establishment of a Diagnostic Center for Amyloidosis in Japan by Kumamoto University (2016)
  • Author(s): Yamashita T, Ando Y
  • Organizer: XVth International Symposium on amyloidosis, Uppsala
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03 – 2016-07-07
  • Int'l Joint Research
• [Presentation] Role of C-terminal portion of transthyretin on amyloid formation (2016)
  • Author(s): Ueda M, Mizuguchi M, Misumi Y, Tasaki M, Suenaga G, Matsumoto S, Mizukami M, Masuda T, Yamashita T, Kluve-Beckerman B, Liepnieks JJ, Benson MD, Ando Y
  • Organizer: XVth International Symposium on amyloidosis, Uppsala
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03 – 2016-07-07
  • Int'l Joint Research
• [Presentation] Occurrence factors and clinical picture of iatrogenic transthyretin amyloidosis after domino liver transplantation, (2016)
  • Author(s): Misumi Y, Oshima T, Ueda M, Yamashita T, Tasaki M, Masuda T, Obayashi K, Ando Y
  • Organizer: XVth International Symposium on amyloidosis, Uppsala
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03 – 2016-07-07
  • Int'l Joint Research
• [Presentation] Multiple nodular pulmonary and subcutaneous amyloidosis associated with Sjögren syndrome. (2016)
  • Author(s): Kinoshita Y, Misumi Y, Ueda M, Tasaki M, Masuda T, Suenaga G, Inoue Y, Obayashi K, Yamashita T, Ando Y
  • Organizer: XVth International Symposium on amyloidosis, Uppsala
  • Place of Presentation: Uppsala, Sweden
  • Year and Date: 2016-07-03 – 2016-07-07
  • Int'l Joint Research
• [Presentation] ここまで治るようになった家族性アミロイドポリニューロパチー 教育コース 「ここまで治る！神経疾患の新たな治療」 (2016)
  • Author(s): 山下太郎, 安東由喜雄
  • Organizer: 第57回日本神経学会学術集会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18 – 2016-05-21
• [Presentation] 家族性アミロイドポリニューロパチーにおける末梢神経障害の軸索興奮性測定による解析 (2016)
  • Author(s): 山下太郎, 三澤園子, 増田曜章, 三隅洋平, 植田光晴, 高松孝太郎, 桑原聡, 安東由喜雄
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18 – 2016-05-21
• [Presentation] 熊本震災における神経内科力 (2016)
  • Author(s): 安東由喜雄
  • Organizer: 第５７回日本神経学会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18 – 2016-05-21
  • Invited
• [Presentation] 抹消神経障害の鑑別と治療の最前線・FAPの治療戦略 (2016)
  • Author(s): 安東由喜雄
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18 – 2016-05-21
• [Presentation] Amyloid formation of C-terminal portion of transthyretin. (2016)
  • Author(s): Ueda M, Mizuguchi M, Misumi Y, Masuda T, Tasaki M, Suenaga G, Inoue Y, Tsuda Y, Nomura T, Kinoshita Y, Matsumoto S, Mizukami M, Yamashita T, Ando Y
  • Organizer: 第57回日本神経学会学術大会
  • Place of Presentation: 神戸
  • Year and Date: 2016-05-18 – 2016-05-21
• [Book] 最新 アミロイドーシスのすべて -診療ガイドライン2017とQ＆A (2017)
  • Author(s): 安東由喜雄、植田光晴、山下太郎、三隅洋平 他
  • Total Pages: 250
  • Publisher: 医歯薬出版株式会社
• [Patent(Industrial Property Rights)] 新規なアミロイド線維生成抑制剤 (2016)
  • Inventor(s): 城野博史、有馬英俊、安東由喜雄、本山敬一、東大志
  • Industrial Property Rights Holder: 国立大学法人熊本大学
  • Industrial Property Rights Type: 特許
  • Industrial Property Number: PCT/JP2016/067373
  • Filing Date: 2016-06-10
  • Overseas