A trial of permanent functional renal allografts : combined therapy using a novel approach involving induction of immune tolerance and MF1 gene transfection

• Project/Area Number: 18390440
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Urology
• Research Institution: Osaka Medical College
• Principal Investigator: AZUMA Haruhito Osaka Medical College, 医学部, 准教授 (40231914)
• Co-Investigator(Kenkyū-buntansha): KATSUOKA Yoji 大阪医科大学, 医学部, 教授 (10051757) ; KIYAMA Satoshi 大阪医科大学, 医学部, 非常勤講師 (10351404) ; TAKAHARA Siro 大阪大学, 医学(系)研究科(研究院), 寄附講座教授 (70179547) ; LI Xiaokang 国立成育医療センター(研究所), 移植、外科研究部, 室長 (60321890) ; 右梅 貴信 大阪医科大学, 医学部, 助手 (90388265)
• Project Period (FY): 2006 – 2009
• Project Status: Completed (Fiscal Year 2008)
• Budget Amount: ¥12,810,000 (Direct Cost: ¥10,800,000、Indirect Cost: ¥2,010,000); Fiscal Year 2008: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2007: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2006: ¥4,100,000 (Direct Cost: ¥4,100,000)
• Keywords: 腎移植 / 免疫寛容 / メトロンファクター / 遺伝子導入 / CTLA4 / ICOS / CD28-superagonist / CD28-B7 / レンチウイルス / MF-1 / HGF / MSP

Research Abstract

ラット腎移植モデルにおいて3種類の抗体"改良型CTLA4-Ig"、"Anti-ICOS-Ig"、および"CD28-SA"を併用することにより免疫寛容を導入し、レンチウイルスをベクタを用いてMF-1遺伝子を移植腎組織に導入し、移植腎を長期的に保護することによって、移植腎を永久生着させることを目的としていたが、3種抗体投与においては、予想に反してCD28-SA単独投与群で最も高い生着延長効果がみられ、また、2匹のレシピエントに抗体投与によると思われる強い全身性の炎症反応を認めた。また、MF-1遺伝子導入については、MF-1発現は見られたが、3種類の抗体投与単独治療群と、3種類の抗体投与+MF-1遺伝子導入併用治療群の間に、有意な治療効果の増強(移植腎組織の改善、生着延長効果)を認めなかった。

Research Products

• [Journal Article] Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts (2008)
  • Author(s): Haruhito Azuma, Isaka Y, Li X, Hunig T, Sakamoto T, Nohmi H, Takabatake Y, Mizui M, Kitazawa Y, Ichimaru N, Ibuki N, Ubai T, Inamoto T, Katsuoka Y, Takahara S
  • Journal Title: Am J Transplant 8(10) Pages: 2004-2014
• [Journal Article] Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts (2008)
  • Author(s): Azuma H, Isaka Y, et.al.
  • Journal Title: Am J Transplant 8(10) Pages: 2004-2014
• [Journal Article] Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts. (2008)
  • Author(s): Azuma H, Isaka Y, Li X, Hunig T, Sakamoto T, Nohmi H, Takabatake Y, Mizui M, Kitazawa Y, Ichimaru N, Ibuki N, Ubai T, Inamoto T, Katsuoka Y, Takahara S.
  • Journal Title: Am J Transplant. 10 Pages: 2004-2014
  • Peer Reviewed
• [Journal Article] Development of immunoglobulin A nephropathy- like disease in beta-1,4-galactosyltransferase-I-deficient mice (2007)
  • Author(s): Nishie T, Miyaishi O, Azuma H, Kameyama A, Naruse C, Hashimoto N, Yokoyama H, Narimatsu H, Wada T, Asano M.
  • Journal Title: Am J Pathol 170 Pages: 447-456
  • Peer Reviewed
• [Journal Article] Infiltration of H-2d-specific cytotoxic macrophage with unique morphology into rej ecti on site of allografted meth A (H-2d) tumor cells in C57BL/6(H-2b) mice (2007)
  • Author(s): Nomi H, Tashiro-Yamaji J, Miura-Takeda S, Shimizu T, Azuma H, Ueda H, Katsuoka Y, Kubota T, Yoshida R.
  • Journal Title: Microbiol Immunol 51 Pages: 297-306
  • Peer Reviewed
• [Journal Article] Development of IgA nephropathy-like disease with high serum IgA levels and increased proportion of polymeric IgA in Beta-1,4-galactosylt ransferase-deficient mice (2007)
  • Author(s): Nishie T, Miyaishi O, Azuma H, Kameyama A, Naruse C, Hashimoto N, Yokoyama H, Narimatsu H, Wada T, Asano M.
  • Journal Title: Contrib Nephrol 157 Pages: 125-128
  • Peer Reviewed
• [Journal Article] Acute rejection of allografted CTL-susceptible leukemia cells from perforin/Fas ligand double-deficient mice (2007)
  • Author(s): Nomi H, Tashiro-Yamaji J, Yamamoto Y, Miura-Takeda S, Miyoshi-Higashino M, Takahashi T, Azuma H, Ueda H, Katsuoka Y, Kubota T, Yoshida R.
  • Journal Title: J Immunol 179 Pages: 2180-2186
  • Peer Reviewed
• [Journal Article] Development of immunoglobulin A nephropathy-like disease in beta-1,4-galactosyltransgerase-I-deficient mice. (2007)
  • Author(s): Nishie T, Miyaishi O, Azuma H, Kameyama A, Naruse C, Hashimoto N, Yokoyama H, Narimatsu H, Wada T, Asano M
  • Journal Title: AM J Pathol. 170(2) Pages: 447-456
• [Journal Article] Reduction in chronic allograft nephropathy by inhibition of p38 mitogen-activated protein kinase. (2006)
  • Author(s): Wada T, Azuma H, Furuichi K, Sasaki N, Kitagawa K, Iwata Y, Matsushima K, Takahara S, Yokoyama H, Kaneko S
  • Journal Title: Am J Nephrol. 26(4) Pages: 319-325
• [Presentation] Donor specific tolerance induced by Superagonistic CD28 antibody in rat renal allografts (2008)
  • Author(s): Azuma H
  • Organizer: 第7回日韓移植フォーラム
  • Place of Presentation: Soul, Korea
  • Year and Date: 2008-10-10
• [Presentation] TRANSFECTION OF NFKB DECOY OLIGODEOXYNUCLEOTIDES USING"EFFICIENT ULTRASOUND-GENE TRANSFER" INTO DONOR KIDNEYS PROLONGED SURVIVAL OF RAT RENAL ALLOGRAFTS PROLONGED SURVIVAL OF RAT RENAL ALLOGRAFTS (2008)
  • Author(s): Azuma H
  • Organizer: XXII International Congress of The Transplantation Society
  • Place of Presentation: Sydney, Australia
  • Year and Date: 2008-08-11
• [Presentation] Transfection of NFkB Decoy Oligodeoxynucleotides Using Efficient Ultrasound-mediated Gene Transfer into Donor Kidneys Prolonged Survival of Rat Renal Allografts (2008)
  • Author(s): Azuma H, Nomi H, et.al.
  • Organizer: International Congress of The Transplantation Society
  • Place of Presentation: Sydney Australia
  • Year and Date: 2008-08-11
• [Presentation] Transfection of NFkB Decoy Oligodeoxynucleotides Using "Efficient Ultrasound-mediated Gene Transfer" into Donor Kidneys Prolonged Survival of Rat Renal Allografts (2008)
  • Author(s): H. Azuma, H. nomi, N. Ibuki, N. Tomita, R. Morishita, S. Horie, S. Takahara, Y. Katsuoka.
  • Organizer: XXII International Congress of The Transplantation Society
  • Place of Presentation: Sydney, Autralia
  • Year and Date: 2008-08-11
• [Presentation] 新しい発想による免疫抑制:CD28スーパーアドニスト抗体による免疫寛容導入 (2007)
  • Author(s): 東 治人、高原 史郎、奥山 明彦、能見 勇人、勝岡 洋治
  • Organizer: 第95回日本泌尿器科学会総会
  • Place of Presentation: 神戸ポートピアホテル借楽2
  • Year and Date: 2007-04-17
• [Presentation] 前立腺癌転移における神経伝達物質"GABA"の関与:MMP発現誘発を介して転移を促進 (2007)
  • Author(s): 東 治人、稲元 輝生、坂元 武、木山 賢、右梅 貴信、古武 彌嗣、高原 健、浜田 修史、伊夫 貴直和、瀬川 直樹、勝岡 洋治
  • Organizer: 第95回日本泌尿器科学会総会
  • Place of Presentation: 神戸国際展示場1号館2F
  • Year and Date: 2007-04-14