Xenotransplantation from GalT-KO miniture swine to baboon in tolerance induction protocol

• Project/Area Number: 20591900
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Nippon Medical School
• Principal Investigator: SHIMIZU Akira Nippon Medical School, 医学部, 准教授 (00256942)
• Co-Investigator(Kenkyū-buntansha): MASUDA Yukinari 日本医科大学, 医学部, 講師 (70173755)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000); Fiscal Year 2010: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2009: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2008: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000)
• Keywords: 腎臓移植 / 異種移植 / 拒絶反応 / 自然抗原ノックアウト / 心臓移植 / 急性拒絶反応 / 慢性拒絶反応 / 血栓性微小血管症 / 前臨床実験 / ヒヒ / 異腫移植

Research Abstract

Xenotransplantation could provide a solution to the critical shortage of organs for transplantation in humans. In attempt to prevent hyperacute rejection (HAR) and acute humoral xenograft rejection (AHXR), α1,3-galactosyltransferase gene knockout (GalT-KO) pigs have been produced in Massachusetts General Hospital, Boston, USA. In heart xenotransplantation from GalT-KO pig into baboon, heterotopic heart grafts could beat in abdominal cavity by 179 days (median 78 days). In kidney xenotransplantation, GalT-KO kidney grafts rejected by day 34 in chronic immunosuppression protocol, but grafts could survive up to 83 days in tolerance inducing protocol. GalT-KO heart and kidney xenografts did not develop hyperacute rejection. However, all GalT-KO heart and kidney grafts in the chronic immunosuppression group were rejected by AHXR with thrombotic microangiopathy. Acute cellular xenograft rejection (ACXR) and chronic rejection also developed. However, in the kidney grafts in tolerance inducing protocol, AHRX, ACXR, and chronic rejection could not be detected in the grafts. Therefore, we conclude that the tolerance inducing protocol is necessary for success the heart and kidney xenotransplantation from GalT-KO pig into baboons.

Research Products

• [Journal Article] Inhibition of matrix metalloproteinases reduces ischemia-reperfusion acute kidney injury. (2011)
  • Author(s): Kunugi S, Shimizu A, Kuwahara N, Du X, Takahashi M, Terasaki Y, Fujita E, Mii A, Nagasaka S, Akimoto T, Masuda Y, Fukuda Y
  • Journal Title: Lab Invest Volume: 91 Pages: 170-180
  • Peer Reviewed
• [Journal Article] Histopathology of xenografts in pig to non-human primate discordant xenotransplantation. (2010)
  • Author(s): Shimizu A, Yamada K
  • Journal Title: Clin Transplant 24 Suppl 22 Pages: 11-15
• [Journal Article] Early humoral-mediated graft injuries in ABO-incompatible kidney transplantation in human beings. (2010)
  • Author(s): Sekijima M, Shimizu A, Ishii Y, Kudo S, Horita S, Nakajima I, Fuchinoue S, Teraoka S
  • Journal Title: Transplant Proc 42 Pages: 789-790
• [Journal Article] Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation. (2010)
  • Author(s): Ishii E, Shimizu A, Kuwahara N, Arai T, Kataoka M, Wakamatsu K, Ishikawa A, Nagasaka S, Fukuda Y
  • Journal Title: Transplant Proc 42 Pages: 4282-4285
• [Journal Article] Inhibition of capillary repair in proliferative glomerulonephritis results in persistent glomerular inflammation with glomerular sclerosis. (2010)
  • Author(s): Masuda Y, Shimizu A, Kataoka M, Arai T, Ishikawa A, Du X, Saito SK, Aki K, Nagasaka S, Mii A, Fujita E, Fukuda Y
  • Journal Title: Lab Invest 90 Pages: 1468-1481
• [Journal Article] Beneficial Effects of Perioperative Low-Dose Inhaled Carbon Monoxide on Pulmonary Allograft Survival in MHC-Inbred CLAWN Miniature Swine. (2010)
  • Author(s): Sahara H, Shimizu A, Setoyama K, Oku M, Okumi M, Nishimura H, Oriyanhan W, Tasaki M, Scalea J, Wada H, Bando T, Date H, Yamada K
  • Journal Title: Transplantation 90 Pages: 1336-1343
• [Journal Article] Reversal of age-related thymic involution by an LHRH agonist in miniature swine. (2010)
  • Author(s): Hirakata A, Okumi M, Griesemer AD, Shimizu A, Nobori S, Tena A, Moran S, Arn S, Boyd RL, Sachs DH, Yamada K
  • Journal Title: Transpl Immunol 24 Pages: 76-81
• [Journal Article] Prolonged survival of GalT-KO swine skin on baboons. (2010)
  • Author(s): Weiner J, Yamada K, Ishikawa Y, Moran S, Etter J, Shimizu A, Smith RN, Sachs DH
  • Journal Title: Xenotransplantation 17 Pages: 147-152
• [Journal Article] Tolerance and long-lasting peripheral chimerism after allogeneic intestinal transplantation in MGH miniature swine. (2010)
  • Author(s): Ishikawa Y, Hirakata A, Griesemer AD, Etter J, Moran S, Weiner J, Shimizu A, Yamada K
  • Journal Title: Transplantation 89 Pages: 417-426
• [Journal Article] Histopathology of xenografts in pig to non-human primate discordant xenotransplantation. (2010)
  • Author(s): Shimizu A, Yamada K
  • Journal Title: Clin Transplant Volume: 24 Suppl22 Pages: 11-15
• [Journal Article] Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation (2010)
  • Author(s): Ishii E, Shimizu A, Kuwahara N, Arai T, Kataoka M, Wakamatsu K, Ishikawa A, Nagasaka S, Fukuda Y
  • Journal Title: Transplant Proc Volume: 42 Pages: 4282-4285
  • Peer Reviewed
• [Journal Article] Results of gal-knockout porcine thymokidney xenografts. (2010)
  • Author(s): Griesemer AD, Hirakata A, Shimizu A, Moran S, Tena A, Iwaki H, Ishikawa Y, Schule P, Arn JS, Robson SC, Fishman JA, Sykes M, Sachs DH, Yamada K
  • Journal Title: Transplantation 89 Pages: 417-426
  • Peer Reviewed
• [Journal Article] Results of gal-knockout porcine thymokidney xenografts. (2009)
  • Author(s): Griesemer AD, Hirakata A, Shimizu A, Moran S, Tena A, Iwaki H, Ishikawa Y, Schule P, Arn JS, Robson SC, Fishman JA, Sykes M, Sachs DH, Yamada K
  • Journal Title: Am J Transplant 9 Pages: 2669-2678
• [Journal Article] Upregulation of CD59 : potential mechanism of accommodation in a large animal model. (2009)
  • Author(s): Griesemer AD, Okumi M, Shimizu A, Moran S, Ishikawa Y, Iorio J, Arn JS, Yamada K
  • Journal Title: Transplantation 87 Pages: 1308-1317
• [Journal Article] Upregulation of CD59 : potential mechanism of accommodation in a large animal model. (2009)
  • Author(s): Griesemer AD, Okumi M, Shimizu A, Moran S, Ishikawa Y, Iorio J, Arn JS, Yamada K.
  • Journal Title: Transplantation 87 Pages: 1308-1317
  • Peer Reviewed
• [Journal Article] シクロスポリン腎毒性(シクロスポリン腎症)の進展過程における腎微小血管傷害 (2009)
  • Author(s): 清水章, 益田幸成
  • Journal Title: 今日の移植 22 Pages: 667-673
• [Journal Article] Rejection of cardiac xenografts transplanted from a1,3-galactosyltransferase gene-knockout (GalT-KO) pigs to baboons. (2008)
  • Author(s): Hisashi Y, Yamada K, Kuwaki K, Tseng Y-L, Dor FJMF, Houser SL, Robson SC, Schuurman H-J, Cooper DKC, Sachs DH, Colvin RB, Shimizu A
  • Journal Title: Am J Tranplant 8 Pages: 2516-2526
• [Journal Article] Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alpha1,3-galactosyltransferase gene-knockout pigs in baboons. (2008)
  • Author(s): Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, Robson SC, Schuurman HJ, Cooper DK, Sachs DH, Yamada K, Colvin RB
  • Journal Title: Am J Pathol 172 Pages: 1471-1481
• [Journal Article] Pigislet xenograft rejection in a mouse model with an established human immune system. (2008)
  • Author(s): Tonomura N, Shimizu A, Wang S, Yamada K, Tchipashvili V, Weir GC, Yang YG
  • Journal Title: Xenotransplantation 15 Pages: 129-135
• [Journal Article] Antigen-specific human T-cell responses and T cell-dependent production of human antibodies in a humanized mouse model. (2008)
  • Author(s): Tonomura N, Habiro K, Shimizu A, Sykes M, Yang YG
  • Journal Title: Blood 111 Pages: 4293-4296
• [Journal Article] Thrombotic microangiopathy associated with humoral rejection of cardiac xenografts from alphal, 3-galactosyltransferase gene-knockoutpigs in baboons (2008)
  • Author(s): Shimizu A, Hisashi Y, Kuwaki K, Tseng YL, Dor FJ, Houser SL, Robson SC, Schuurman HJ, Cooper DK, Sachs DH, Yamada K, Colvin RB
  • Journal Title: Am J Pathol 172 Pages: 1471-1481
  • Peer Reviewed
• [Journal Article] Rejection of cardiac xenografts transplanted from alphal, 3-galactosyl-transferase gene-knockout (GalT-KO)pigs to baboons (2008)
  • Author(s): Hisashi Y, Yamada K, Kuwaki K, Tseng YL, Dor FJ, Houser SL, Robson sc, Schuurman HJ, Cooper DK, Sachs DH, Colvin RB, Shitnizu A.
  • Journal Title: Am J Transplant 8 Pages: 2516-2526
  • Peer Reviewed
• [Presentation] The pathological characteristics of acute antibody-mediated rejection in DA to Lewis ratorthotopic liver transplantation (2010)
  • Author(s): Shimiuz A, Ishii E, Kuwahara N, Arai T, Kataoka M, Fukuda Y
  • Organizer: XXIII International Congress of The Transplantation Society
  • Place of Presentation: Vancouver, Canada
  • Year and Date: 2010-08-15
• [Presentation] Acute kidney injury during hepatic failure in rats. (2010)
  • Author(s): Shimizu A, Ishii E, Ishikawa A, Arai T, Kuwahara N, Masuda Y, Nagasaka S, Fukuda Y
  • Organizer: 2010 Renal Week in Denver
  • Place of Presentation: Colorado
• [Presentation] The pathological characteristics of acute antibody-mediated rejection in DA to Lewis rat orthotopic liver transplantation. (2010)
  • Author(s): Shimizu A, Ishii E, Kuwahara N, Arai T, Kataoka M, Fukuda Y
  • Organizer: XXIII International Congress of The Transplantation Society
  • Place of Presentation: Vancouver
• [Presentation] Chronic antibody-mediated rejection in rat orthotopic liver transplantation. (2010)
  • Author(s): Ishii E, Shimizu A, Arai T, Kataoka M, Ishikawa A, Wakamatsu K, Nagasaka S, Fukuda Y
  • Organizer: XXIII International Congress of The Transplantation Society
  • Place of Presentation: Vancouver
• [Presentation] Lymhangiogenesis associated with acute cellular rejection in rat liver transplantation. (2010)
  • Author(s): Ishii E, Shimizu A, Kuwahara N, Arai T, Kataoka M, Wakamatsu K, Ishikawa A, Nagasaka S, Fukuda Y
  • Organizer: XXIII International Congress of The Transplantation Society
  • Place of Presentation: Vancouver
• [Presentation] 大動物からヒトへの臨床応用:αGa1ノックアウトMGHミニブタからヒヒへの異種腎移植の病理像 (2009)
  • Author(s): 清水章
  • Organizer: 移植腎病理研究会・第13回学術集会
  • Place of Presentation: 東京
  • Year and Date: 2009-07-18
• [Presentation] 腎移植の新しい治療戦略:大動物からヒトへの臨床応用,aGalノックアウトMGHミニブタからヒヒへの異種腎移植の病理像, (2009)
  • Author(s): 清水章
  • Organizer: 移植腎病理研究会・第13回学術集会
  • Place of Presentation: 東京
• [Presentation] The pathological characteristics of acute antibody-mediated rejection in DA to Lewis rat orthotopic liver transplantation. (2009)
  • Author(s): Shimiuz A, Ishii E, Kuwahara N, Arai T, Kataoka M, Fukuda Y
  • Organizer: The American Transplant Congress.
  • Place of Presentation: Boston