The pathological and immunological characteristics of grafts with long-term acceptance in rat liver transplantation

• Project/Area Number: 26461931
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: General surgery
• Research Institution: Nippon Medical School
• Principal Investigator: Ishii Eiichi 日本医科大学, 大学院医学研究科, 研究生 (00193243)
• Co-Investigator(Kenkyū-buntansha): 清水 章 日本医科大学, 大学院医学研究科, 大学院教授 (00256942)
• Project Period (FY): 2014-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000); Fiscal Year 2016: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2015: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2014: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 移植 / 肝臓移植 / ラット / 免疫寛容 / 拒絶反応 / 病理 / microRNA / 制御性T細胞 / 動物実験 / 免疫応答 / T細胞性拒絶反応 / 抗体関連型拒絶反応

Outline of Final Research Achievements

In DA-to-Lewis rat liver transplantation, the progressive acute T cell- and antibody-mediated rejection developed by day 11 with irreversible graft failure. In DA-to-PVG rat liver transplantation, the transient acute T cell-mediated inflammation occurred between day 7 to day 14, but reduced on day 21 and subsided on day 100 with stable graft functions. The infiltrates in DA-PVG accepting grafts at day 7 to day 14 differed from that in DA-Lew rejecting grafts in certain features, including less infiltration by T cells and macrophages, many Foxp3+Tregs, less levels of Th1 (IL-12, IFN-γ, TNF-α) and high expression of Th2 (IL-4, IL-10) cytokines. In addition, 193 microRNAs were up-regulated or down-regulated in rejecting or accepting grafts when compared with those in normal DA liver. We concluded that the immunological reactions in grafts with rejection or long-term acceptance may be regulated by specific Th1 and Th2 cytokines and several inflammatory miRNAs.

Research Products

• [Journal Article] Tolerance of Vascularized Islet-Kidney Transplants in Rhesus Monkeys. (2017)
  • Author(s): Pathiraja V, Villani V, Tasaki M, Matar AJ, Duran-Struuck R, Yamada R, Moran SG, Clayman ES, Hanekamp J, Shimizu A, Sachs DH, Huang CA, Yamada K.
  • Journal Title: Am J Transplant Volume: 17 Issue: 1 Pages: 91-102
  • DOI: 10.1111/ajt.13952
  • Peer Reviewed
• [Journal Article] Adoptive Transfer of Renal Allograft Tolerance in a Large Animal Model. (2016)
  • Author(s): Villani V, Yamada K, Scalea JR, Gillon BC, Arn JS, Sekijima M, Tasaki M, Cormack TA, Moran SG, Torabi R, Shimizu A, Sachs DH.
  • Journal Title: Am J Transplant Volume: 16 Issue: 1 Pages: 317-324
  • DOI: 10.1111/ajt.13424
  • Peer Reviewed
• [Journal Article] Currently available useful immunohistochemical markers of renal pathology for the diagnosis of renal allograft rejection (2015)
  • Author(s): Kanzaki G, Shimizu A
  • Journal Title: Nephrology Volume: 20 Suppl(2) Issue: S2 Pages: 9-15
  • DOI: 10.1111/nep.12460
  • Peer Reviewed
• [Journal Article] Phospholipase A2 receptor positive membranous nephropathy long after living donor kidney transplamtation between identical twins. (2015)
  • Author(s): Saito H, Hamasaki Y, Tojo A, Shintani Y, Shimizu A, Nangaku M.
  • Journal Title: Nephrology Volume: 20(suppl. 2) Issue: S2 Pages: 101-104
  • DOI: 10.1111/nep.12458
  • Peer Reviewed / Open Access
• [Journal Article] High incidence of xenogenic bone marrow engraftment in pig-to-baboon intra-bone bone marrow transplantation (2015)
  • Author(s): Tasaki M, Wamala I, Tena A, Villani V, Sekijima M, Pathiraja V, Wilkinson RA, Pratts S, Cormack TA, Clayman E, Arn JS, Shimizu A, Fishman JA, Sachs DH, Yamada K
  • Journal Title: Am J Transplant Volume: 15 Issue: 4 Pages: 974-983
  • DOI: 10.1111/ajt.13070
  • Peer Reviewed
• [Presentation] microRNA in acute liver graft rejection in DA to Lewis rat orthotopic liver transplantation (2014)
  • Author(s): Ishii E, Kuwahara N, Arai T, Kataoka M, Nagasaka S, Masuda Y, Shimiuz A
  • Organizer: 2014 World Transplant Congress
  • Place of Presentation: San Francisco, California
  • Year and Date: 2014-07-26 – 2014-07-31
• [Presentation] 腎局在樹状細胞の表現型解析 (2014)
  • Author(s): 永坂真也, 岩堀 徹, 肥後清一郎, 神崎 剛, 梶本雄介, 益田幸成, 清水 章
  • Organizer: 日本腎臓学会学術総会 (第57回)
  • Place of Presentation: パシピィッコ横浜
  • Year and Date: 2014-07-04 – 2014-07-06
• [Book] Xenotransplantation, Pathobiology of Human Disease (ed. Linda M, McManus, Richard N. Mitchell) (2014)
  • Author(s): Shimizu A, Kanzaki G
  • Publisher: Elsevier