A proteomic approach to identify biomarkers to discriminate between chronic rejection and immunological tolerance after liver transplantation

• Project/Area Number: 26460450
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Human pathology
• Research Institution: Kyoto University
• Principal Investigator: Miyagawa-Hayashino Aya 京都大学, 医学研究科, 特定准教授 (90432385)
• Co-Investigator(Kenkyū-buntansha): 鶴山 竜昭 京都大学, 医学研究科, 特定教授 (00303842)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,420,000 (Direct Cost: ¥3,400,000、Indirect Cost: ¥1,020,000); Fiscal Year 2016: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2015: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2014: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 肝移植 / 慢性拒絶 / 免疫寛容 / バイオマーカー / 慢性拒絶反応 / プロテオーム解析 / 早期診断 / 細胆管

Outline of Final Research Achievements

Chronic rejection (CR) remains a serious cause of liver allograft dysfunction. The biomarkers to predict the patients’ outcome are necessary to determine the immunosuppressive strategies early after transplantation. Using antibody microarray, we provided evidence about the down-expression of STK17A in CR. STK17A is a member of the death-associated protein kinase family. Its biological significance in the liver is unknown. We found a new location for STK17A in bile canaliculi. During the evolution of CR, the staining pattern of bile canalicular STK17A gradually changed from diffuse linear to focal intermittent. The alteration in the expression pattern of STK17A in bile canaliculi may help identify early stages of the disease. We applied liver tissue samples of tolerance and CR to liquid chromatography mass spectrometry to investigate the biomarker to discriminate between the tolerance and CR early after LT and the validation study for candidate proteins has been undertaken.

Research Products

• [Journal Article] Antibodies that React with Liver Tissue and Donor-specific anti-HLA Antibodies in Pediatric Idiopathic Posttransplantation Hepatitis (2017)
  • Author(s): Hirata Y, Yoshizawa A, Egawa H, Ueda D, Okamoto S, Okajima H, Yurugi K, Hishida R, Hirai H, Miyagawa-Hayashino A, Maekawa T, Haga H, Uemoto S
  • Journal Title: Transplantation Volume: 印刷中 Issue: 5 Pages: 1074-1083
  • DOI: 10.1097/tp.0000000000001653
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Loss of Hep Par 1 immunoreactivity in the livers of patients with carbamoyl phosphate synthetase 1 deficiency (2016)
  • Author(s): Yamaguchi M, Kataoka TR, Shibayama T, Fukuda A, Nakazawa A, Minamiguchi S, Sakurai T,Miyagawa-Hayashino A, Yorifuji T, Kasahara M, Uemoto S, Haga H
  • Journal Title: Pathol Int Volume: 66 Issue: 6 Pages: 333-336
  • DOI: 10.1111/pin.12414
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Abnormal Localization of STK17A in Bile Canaliculi in Liver Allografts: An Early Sign of Chronic Rejection. (2015)
  • Author(s): Ozeki M, Salah A, Aini W, Tamaki K, Haga H, Miyagawa-Hayashino A
  • Journal Title: PLoS One Volume: 10 Issue: 8 Pages: e0136381-e0136381
  • DOI: 10.1371/journal.pone.0136381
  • NAID: 120005678181
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Necrostatin-1 protects against reactive oxygen species (ROS)-induced hepatotoxicity in acetaminophen-induced acute liver failure. (2014)
  • Author(s): Takemoto K, Hatano E, Iwaisako K, Takeiri M, Noma N, Ohmae S, Toriguchi K, Tanabe K, Tanaka H, Seo S, Taura K, Machida K, Takeda N, Saji S, Uemoto S, Asagiri M.
  • Journal Title: FEBS Open Bio. Volume: 6 Issue: 2 Pages: 777-87
  • DOI: 10.1016/j.jss.2014.08.052
  • NAID: 120005496668
  • Peer Reviewed / Open Access
• [Journal Article] Pleuroparenchymal fibroelastosis and non-specific interstitial pneumonia: frequent pulmonary sequelae of haematopoietic stem cell transplantation (2014)
  • Author(s): Takeuchi Y, Miyagawa-Hayashino A, Chen F, Kubo T, Handa T, Date H, Haga H
  • Journal Title: Histopathology Volume: 66 Issue: 4 Pages: 536-44
  • DOI: 10.1111/his.12553
  • Peer Reviewed / Open Access
• [Journal Article] Lung transplantation for pleuroparenchymal fibroelastosis after chemotherapy (2014)
  • Author(s): Chen F, Matsubara K, Miyagawa-Hayashino A, Tada K, Handa T, Yamada T, Sato M, Aoyama A, Date H
  • Journal Title: Ann Thorac Surg Volume: 98 Issue: 5 Pages: e115-e117
  • DOI: 10.1016/j.athoracsur.2014.07.045
  • Peer Reviewed
• [Journal Article] Successful single-lung transplantation for multicentric castleman disease (2014)
  • Author(s): Morimura Y, Chen F, Kinjo T, Miyagawa-Hayashino A, Kubo T, Yamada T, Sato M, Aoyama A, Date H
  • Journal Title: Ann Thorac Surg Volume: 98 Issue: 3 Pages: e63-e65
  • DOI: 10.1016/j.athoracsur.2014.06.074
  • Peer Reviewed
• [Journal Article] Accelerated telomere reduction and hepatocyte senescence in tolerated human liver allografts (2014)
  • Author(s): Aini W, Miyagawa-Hayashino A, Ozeki M, Adeeb S, Hirata M, Tamaki K, Uemoto S, Haga H
  • Journal Title: Transpl Immunol Volume: 31 Issue: 2 Pages: 55-59
  • DOI: 10.1016/j.trim.2014.06.008
  • NAID: 120005477692
  • Peer Reviewed
• [Journal Article] Neutrophil gelatinase-associated lipocalin in idiopathic pulmonary fibrosis. (2014)
  • Author(s): Ikezoe K, Handa T, Mori K, Watanabe K, Tanizawa K, Aihara K, Tsuruyama T, Miyagawa-Hayashino A, Sokai A, Kubo T, Muro S, Nagai S, Hirai T, Chin K, Mishima M
  • Journal Title: Eur Respir J Volume: 43 Issue: 6 Pages: 1807-1809
  • DOI: 10.1183/09031936.00192613
  • Peer Reviewed
• [Journal Article] Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1 (2013)
  • Author(s): Nakamura K, Hatano E, Miyagawa-Hayashino A, Okuno M, Koyama Y, Narita M, Seo S, Taura K, Uemoto S
  • Journal Title: Liver Int Volume: Nov 29 Issue: 10 Pages: 1473-1487
  • DOI: 10.1111/liv.12420
  • Peer Reviewed
• [Presentation] Large cell transformationを来した菌状息肉症4例における検討 (2016)
  • Author(s): 前田 紘奈, 桜井 孝規, 宮川 文, 吉澤 明彦, 南口 早智子, 羽賀 博典
  • Organizer: 日本病理学会
  • Place of Presentation: 仙台市、宮城
  • Year and Date: 2016-05-11
• [Presentation] 類血管腫型線維性組織球腫の 2 例 (2016)
  • Author(s): 岩元 竜太、宮川 文、桜井 孝規、西村 啓介、羽賀 博典
  • Organizer: 日本病理学会
  • Place of Presentation: 仙台市、宮城
  • Year and Date: 2016-05-11
• [Presentation] 小児肝移植長期生存例における術後合併症の組織所見 (2015)
  • Author(s): 宮川（林野） 文
  • Organizer: 第 7 回小児肝臓・肝移植セミナー
  • Place of Presentation: 東京医大
  • Year and Date: 2015-09-12
  • Invited
• [Presentation] 周囲に娘結節を伴った腹腔内炎症性筋線維芽細胞性腫瘍の一例 (2015)
  • Author(s): 古川敦行、宮川 文、肥田候矢、南口早智子、桜井孝規、羽賀博典
  • Organizer: 第104回日本病理学会総会
  • Place of Presentation: 名古屋市
  • Year and Date: 2015-04-30
• [Presentation] A演説 生体肝移植後長期合併症と免疫寛容、グラフトの老化との関連 (2014)
  • Author(s): 宮川 文[林野], 鶴山 竜昭, 羽賀 博典
  • Organizer: 第60回日本病理学会 秋期特別総会
  • Place of Presentation: 那覇市
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] カルバモイルリン酸合成酵素欠損症における HepPar1 染色性の検討 (2014)
  • Author(s): 山口真希、柴山隆宏、向井雄一、南口早智子、桜井孝規、羽賀博典、宮川 文、中澤温子、依藤 亨
  • Organizer: 第60回日本病理学会 秋期特別総会
  • Place of Presentation: 那覇市
  • Year and Date: 2014-11-20 – 2014-11-21
• [Presentation] HLA 3座不一致生体肝移植術後、急性拒絶反応を経て移植片対宿主病を発症した1剖検例 (2014)
  • Author(s): 竹内 康英, 片岡 竜貴, 宮川 文, 吾拉木江 艾尼, 羽賀 博典
  • Organizer: 第60回日本病理学会 秋期特別総会
  • Place of Presentation: 那覇市
  • Year and Date: 2014-11-20 – 2014-11-21
• [Book] Nakanuma Y ed. Pathology of the Bile Duct (2017)
  • Author(s): Miyagawa-Hayashino A, Haga H
  • Publisher: Springer Nature, Berlin, Germany