Establishment of immune cell therapy for transplant medical application

• Project/Area Number: 20390349
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: General surgery
• Research Institution: National Research Institute for Child Health and Development
• Principal Investigator: LI Xiaokang 独立行政法人国立成育医療研究センター, 研究所, RI管理室長 (60321890)
• Co-Investigator(Kenkyū-buntansha): TAKAHARA Shiro 大阪大学, 大学院・医学研究科・先端移植基盤医療学, 教授 (70179547) ; KIMURA Hiromitsu (独)国立成育医療研究センター, 研究所, 共同研究管理室長 (80115477)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000); Fiscal Year 2010: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2009: ¥2,860,000 (Direct Cost: ¥2,200,000、Indirect Cost: ¥660,000); Fiscal Year 2008: ¥12,350,000 (Direct Cost: ¥9,500,000、Indirect Cost: ¥2,850,000)
• Keywords: 移植・再生医療 / 遺伝子 / 細胞・組織 / 免疫寛容 / 細胞療法 / バイオマーカー

Research Abstract

The results of the present research project are summarized : 1) The supCD28mAb can preferentially expand nTregs, which induced a potent inhibition of the lethality of GvHD via an antigen-specific manner. These data also provide evidence that GvHD is associated with a decrease of Foxp3 nTregs in the periphery of the host. The determination of the Foxp3 Tregs can be a helpful tool to discriminate the severity and lethality of GvHD after allogeneic stem cell transplantation ; 2) Our rat model showed differences in the suppression of lymphocyte proliferation and GvHD prevention between the short-term cultured conventional BM-MSCs and cloned MSCs and the mechanisms of functional MSCs still remain to be identified ; 3) We demonstrated that utilizing the multiplex PCR GeXP system, to identify a set of immunoregulatory genes which provides sensitivity and specificity for diagnosing rejection and tolerance in mouse hepatic and cardiac transplant models. These data may usher in an era of increased utilization of these gene-based tests for the routine diagnosis of rejection and/or tolerance and thus may be a useful new technology for identification of new biomarkers for the diagnosis of allograft rejection and tolerance in transplant patients.

Research Products

• [Journal Article] The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis (2011)
  • Author(s): Chen J, Xie L, Toyama S, Hunig T, Takahara S, Li X-K, Zhong L
  • Journal Title: Int Immunopharmacol Volume: 11(5) Pages: 610-7
  • Peer Reviewed
• [Journal Article] The effects of Foxp3-expressing regulatory T cells expanded with CD28 superagonist antibody in DSS-induced mice colitis (2011)
  • Author(s): Chen J, et al
  • Journal Title: Int Immunopharmacol Volume: 11(5) Pages: 610-617
  • Peer Reviewed
• [Journal Article] CD28 superagonist-induced regulatory T cell expansion ameliorates mesangioprolifera tive glomerulonephritis in rats (2010)
  • Author(s): Miyasato K, Takabatake Y, Kaimori J, Kimura T, Kitamura H, Kawachi H, Li X-K, Hunig T, Takahara S, Rakugi H, Isaka Y
  • Journal Title: Clin Exp Nephrol Volume: 5(1) Pages: 50-7
  • Peer Reviewed
• [Journal Article] Induction of Donor-Specific Tolerance Using Superagonistic CD28 Antibody in Rat Renal Allografts : Regulatory T-Cell Expansion Before Engraftment May Be Important (2010)
  • Author(s): Azuma H, Isaka Y, Nomi H, Inamoto T, Li X-K, H. unig T, Takabatake Y, Ichimaru N, Ibuki N, Matsumoto K, Ubai T, Katsuoka Y, Takahara S
  • Journal Title: Transplantation Volume: 90(12) Pages: 1328-1335
  • Peer Reviewed
• [Journal Article] Prevention of graft-versus-host diseases by in vivo supCD28mAb-expanded antigen-specific nTreg cells (2010)
  • Author(s): Kitazawa Y, Li X-K, Liu Z, Kimura H, Isaka Y, Hunig T, Takahara S
  • Journal Title: Cell Transplant Volume: 19(6) Pages: 765-74
  • Peer Reviewed
• [Journal Article] PD1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft (2010)
  • Author(s): Morita M, Fujino M, Jiang GP, Kitazawa Y, Xie L, Azuma M, Yagita H, Nagao S, Sugioka A, Kurosawa Y, Takahara S, Fung J, Qian S, Lu L, Li X-K
  • Journal Title: Am J Transplant Volume: 10(1) Pages: 40-46
  • Peer Reviewed
• [Journal Article] Induction of Donor-Specific Tolerance Using Superagonistic CD28 Antibody in Rat Renal Allografts : Regulatory T-Cell Expansion Before Engraftment May Be Important. (2010)
  • Author(s): Azuma H, Isaka Y, Nomi H, Inamoto T, Li X-K, Hounig T, Takabatake Y, Ichimaru N, Ibuki N, Matsumoto K, Ubai T, Katsuoka Y, Takahara S.
  • Journal Title: Transplantation 90(12) Pages: 1328-1335
  • Peer Reviewed
• [Journal Article] Prevention of graft-versus-host diseases by in vivo supCD28mAb-expanded antigen-specific nTreg cells. (2010)
  • Author(s): Kitazawa Y, Li X-K, Liu Z, Kimura H, Isaka Y, Hunig T, Takahara S.
  • Journal Title: Cell Transplant 19(6) Pages: 765-774
  • Peer Reviewed
• [Journal Article] PD1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft. (2010)
  • Author(s): Morita M, Fujino M, Jiang GP, Kitazawa Y, Xie L, Azuma M, Yagita H, Nagao S, Sugioka A, Kurosawa Y, Takahara S, Fung J, Qian S, Lu L, Li X-K.
  • Journal Title: Am J Transplant 10(1) Pages: 40-46
  • Peer Reviewed
• [Journal Article] Induction of donor-specific tolerance using superagonistic CD28 antibody in rat renal allografts : regulatory T-Cell expansion before engraftment may be important (2010)
  • Author(s): Azuma H, et al
  • Journal Title: Transplantation Volume: 90(12) Pages: 1328-1335
  • Peer Reviewed
• [Journal Article] Prevention of graft-versus-host diseases by in vivo supCD28m Ab-expanded antigen-specific nTreg cells (2010)
  • Author(s): Kitazawa Y, et al
  • Journal Title: Cell Transplant Volume: 19(6) Pages: 765-774
  • Peer Reviewed
• [Journal Article] CD28 superagonist-induced regulatory T cell expansion ameliorates mesangioproliferative glomerulonephritis in rats (2010)
  • Author(s): Miyasato K, et al
  • Journal Title: Clin Exp Nephrol Volume: 15(1) Pages: 50-57
  • Peer Reviewed
• [Journal Article] PD1/B7-H1 interaction contribute to the spontaneous acceptance of mouse liver allograft (2010)
  • Author(s): Morita M, et al
  • Journal Title: Am J Transplant 10(1) Pages: 40-6
  • Peer Reviewed
• [Journal Article] Superagonist CD28 antibody preferentially expanded Foxp3-expressing nTreg cells and prevented graft-versus-host diseases (2009)
  • Author(s): Kitazawa Y, Fujino M, Li X-K, Xie L, Ichimaru N, Okumi M, Nonomura N, Tsujimura A, Isaka Y, Kimura H, Hunig T, Takahara S
  • Journal Title: Cell Transplant Volume: 18(5) Pages: 627-37
  • Peer Reviewed
• [Journal Article] Immunological behavior of enhanced green fluorescent protein(EGFP) as a minor histocompatibility antigen with a special reference to skin isograft and specific regulation of local graft-versus-host reaction(GvHR) (2009)
  • Author(s): Pan XC, Deng YB, Sugawara Y, Makuuchi M, Okabe M, Ochiya T, Sugiura W, Kitazawa Y, Fuji N, Li X-K, Miyamoto M, Kimura H
  • Journal Title: Immunol Lett Volume: 123(2) Pages: 103-13
  • Peer Reviewed
• [Journal Article] 18F-FDG PET for the Semiquantitative Evaluation of Acute Allograft Rejection and the Immunosuppre ssion Therapy Efficacy in Liver Transplantation Rat Models (2009)
  • Author(s): Tsuji A. B, Morita M, Li X-K, Sogawa C, Sudo H, Sugyo A, Fujino M, Sugioka A, Koizumi M, Saga T
  • Journal Title: J Nucl Med Volume: 50(5) Pages: 827-30
  • Peer Reviewed
• [Journal Article] Superagonist CD28 antibody preferentially expanded Foxp3-expressing nTreg cells and prevented graft-versus-host diseases. (2009)
  • Author(s): Kitazawa Y, Fujino M, Li X-K, Xie L, Ichimaru N, Okumi M, Nonomura N, Tsujimura A, Isaka Y, Kimura H, Hunig T, Takahara S.
  • Journal Title: Cell Transplant 18(5) Pages: 627-637
  • Peer Reviewed
• [Journal Article] Prolongation of rat major histocompatibility complex-compatible cardiac allograft survival during pregnancy. (2009)
  • Author(s): Funeshima-Fuji N, Fujino M, Xie L, Kimura H, Takahara S, Ezaki T, Zhu BT, Li X-K.
  • Journal Title: J Heart Lung Transplant 28(2) Pages: 176-182
  • Peer Reviewed
• [Journal Article] Superagonist CD28 antibody preferentially expanded Foxp3-expressing nTreg cells and prevented graft-versus-host diseases (2009)
  • Author(s): Kitazawa Y, et al
  • Journal Title: Cell Transplant 18(5) Pages: 627-37
  • Peer Reviewed
• [Journal Article] Immunological behavior of enhanced green fluorescent protein(EGFP)as a minor histocompatibility antigen with a special reference to skin isograft and specific regulation of local graft-versus-host reaction(GvHR) (2009)
  • Author(s): Pan XC, et al
  • Journal Title: Immunol Lett 123(2) Pages: 103-13
  • Peer Reviewed
• [Journal Article] 18F-FDG PET for the Semiquantitative Evaluation of Acute Allograft Rejection and the Immunosuppression Therapy Efficacyin Liver Transplantation Rat Models (2009)
  • Author(s): Tsuji A. B, et al
  • Journal Title: J Nucl Med 50(5) Pages: 827-30
  • Peer Reviewed
• [Journal Article] Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts (2008)
  • Author(s): Azuma H, Isaka Y, Li X-K, Hunig T, Skamoto T, Takabatake Y, Mizui M, Kitazawa Y, Ichimaru N, Ibuki N, Inamoto T, Katsuoka Y, Takahara S
  • Journal Title: Am J Transplant Volume: 8(10) Pages: 2004-14
  • Peer Reviewed
• [Journal Article] Foxp3-expressing regulatory T-cells expanded with CD28 superagonist antibody prevent rat cardiac allograft rejection (2008)
  • Author(s): Kitazawa Y, Fujino M, Sakai T, Azumu H, Kimura H, Isaka Y, Takahara S, Hunig T, Abe R, Li X-K
  • Journal Title: J Heart Lung Transplant Volume: 27(4) Pages: 362-71
  • Peer Reviewed
• [Journal Article] Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allografts. (2008)
  • Author(s): Azuma H, Isaka Y, Li X-K, Hunig T, Skamoto T, Takabatake Y, Mizui M, Kitazawa Y, Ichimaru N, Ibuki N, Inamoto T, Katsuoka Y, TakaharaS.
  • Journal Title: Am J Transplant 8(10) Pages: 2004-2014
  • Peer Reviewed
• [Journal Article] Foxp3-expressing regulatory T-cells expanded with CD28 superagonist antibody prevent rat cardiac allograft rejection. (2008)
  • Author(s): Kitazawa Y, Fujino M, Sakai T, Azumu H, Kimura H, Isaka Y, Takahara S, Hunig T, Abe R, Li X-K.
  • Journal Title: J Heart Lung Transplant 27(4) Pages: 362-371
  • Peer Reviewed
• [Journal Article] Foxp3-expressing regulatory T-cells expanded with CD28 superagonist antibody prevent rat cardiac allograft rejection (2008)
  • Author(s): Kitazawa Y, et al
  • Journal Title: J Heart Lung Transplant 27(4) Pages: 362-71
  • Peer Reviewed
• [Journal Article] Superagonistic CD28 antibody induces donor-specific tolerance in rat renal allograft (2008)
  • Author(s): Azuma H, et al
  • Journal Title: Am J Transplant 8(10) Pages: 2004-14
  • Peer Reviewed
• [Journal Article] Bone marrow derived conventional, but not cloned, mesenchymal stem cells suppress lymphocyte proliferation and prevent graft-versus-host disease in rats
  • Author(s): Kitazawa Y, Li X-K, Xie L, Zhu P, Kimura H, Takahara S
  • Journal Title: Cell Transplant Volume: (In press)
  • Peer Reviewed
• [Journal Article] Bone marrow derived conventional, but not cloned, mesenchymal stem cells suppress lymphocyte proliferation and prevent graft-versus-host disease in rats
  • Author(s): Kitazawa Y, et al
  • Journal Title: Cell Transplant Volume: In press
  • Peer Reviewed
• [Presentation] A novel biomarker gene set predicts allograft rejection by multiplex reverse transcription-polymerase chain reaction (2010)
  • Author(s): L. Xie, M. Morita, J. H. Wang, J. J. Chen, S. Nagao, A. Sugioka, S. Takahara, G. A. Levy, and X-K. Li
  • Organizer: 第14回国際免疫学会
  • Place of Presentation: 神戸
• [Presentation] [<18>^F] FDG-PET studies of heterotopic heart transplantation in rats (2010)
  • Author(s): M. Inubushi, N. Hatayama, X-K. Li, Y. N. Jin, M. Koizumi, and T. Saga
  • Organizer: 第40回世界核医学会
  • Place of Presentation: ケープタウン
• [Presentation] 一酸化炭素を用いた新たな臓器保存法の試み (2010)
  • Author(s): 阿部豊文,李小康,畑山直之,角田洋一,蔦原宏一,奥見雅由,矢澤浩治,貝森淳哉,高原史郎
  • Organizer: 第46回日本移植学会総会
  • Place of Presentation: 京都
• [Presentation] Eicosapentaenoic acid attenuate allograft rejection in HLA-B27/EGFP transgenic rat cardiac transplantation model (2010)
  • Author(s): Z. Liu, K. Kato, N. Hatayama, L. Xie, Y. Nagahara, X-K. Li
  • Organizer: 第37回日本臓器保存生物医学会
  • Place of Presentation: 新潟
• [Presentation] 肝臓移植による先天性代謝疾患の新規治療法の開発 (2010)
  • Author(s): 外山扇雅,右田王介,国枝哲男,長原礼宗,奥山虎之,李小康
  • Organizer: 第37回日本臓器保存生物医学会
  • Place of Presentation: 新潟
• [Presentation] ラット摘出心臓によるCOを用いた高圧乾燥保存法の保存限界とメカニズム (2010)
  • Author(s): 畑山直之,梨井康,内藤宗和,小嶋智弘,関邦博
  • Organizer: 第37回日本臓器保存生物医学会
  • Place of Presentation: 新潟
• [Presentation] A novel biomarker gene set predicts allograft rejection by multiplex reverse transcription-polymerase chain reaction. (2010)
  • Author(s): Xie L
  • Organizer: 第14回国際免疫学会
  • Place of Presentation: 神戸
• [Presentation] [^<18>F] FDG-PET studies of heterotopic heart transplantation in rats (2010)
  • Author(s): Inubushi M, et al
  • Organizer: 第40回世界核医学会
  • Place of Presentation: ケープタウン
• [Presentation] A novel biomarker gene set predicts allograft rejection by multiplex reverse transcription-polymerase chain reaction (2010)
  • Author(s): Xie L, et al
  • Organizer: 第19回国際免疫学会
  • Place of Presentation: 神戸
• [Presentation] Bone marrow mesenchymal stem cells suppress lymphocyte proliferation and prevent rat graft-versus-host disease but cloned MSCs are failed (2009)
  • Author(s): Kitazawa Y, Li X-K, Kimura H, Isaka Y, Takahara S
  • Organizer: The Okayama 2009 CTS-JSOPMB Joint Conference
  • Place of Presentation: Okayama
• [Presentation] 拒絶反応の非侵襲的診断法としてのFDG-PETの有用性の検討 (2009)
  • Author(s): 森田美和、辻厚至、曽川千鶴、須藤仁美、須堯綾、藤野真之、謝琳、長尾静子、高原史郎、木村廣光、杉岡篤、小泉満、佐賀恒夫、李小康
  • Organizer: 第45回日本移植学会総会
  • Place of Presentation: 東京
• [Presentation] The importance of the PD-1/PD-L1 co stimulatory signal for spontaneous acceptance after mouse liver allografting (2009)
  • Author(s): Morita M, Kitazawa Y, Xie L, Kimura H, Azuma M, Nagao S, Sugioka A, Li X-K
  • Organizer: 第39回日本免疫学会総会
  • Place of Presentation: 大阪
• [Presentation] CD28superagonistを用いた免疫寛容誘導 (2009)
  • Author(s): 李小康、北沢祐介、東治人、猪阪義隆、高原史郎
  • Organizer: 第44回日本移植学会総会
  • Place of Presentation: 大阪
• [Presentation] 移植免疫寛容の誘導・維持機序の解明および免疫制御細胞療法の確立 (2009)
  • Author(s): 李小康
  • Organizer: 第36回日本臨床免疫学会総会
  • Place of Presentation: 東京
• [Presentation] Bone marrow mesenchymal stem cells suppress lymphocyte proliferation and prevent rat graft-versus-host disease but cloned MSCs are failed. (2009)
  • Author(s): Kitazawa Y
  • Organizer: The Okayama 2009 CTS-JSOPMB Joint Conference
  • Place of Presentation: Okayama
• [Presentation] The importance of the PD-1/PD-L1 co stimulatory signal for spontaneous acceptance after mouse liver allografting. (2009)
  • Author(s): Morita M
  • Organizer: 第39回日本免疫学会総会
  • Place of Presentation: 大阪
• [Presentation] Bone marrow mesenchymal stem cells suppress lymphocyte proliferation and prevent rat graft-versus-host disease but cloned MSCs are failed (2009)
  • Author(s): Kitazawa Y, ら
  • Organizer: The Okayama 2009 CTS-JSOPMB Joint Conference
  • Place of Presentation: 岡山
• [Presentation] CD28 superagonist を用いた免疫寛容誘導 (2008)
  • Author(s): 李小康, ら
  • Organizer: 第44回日本移植学会総会
  • Place of Presentation: 大阪
  • Year and Date: 2008-09-19
• [Presentation] The requirement of the B7-H1 for spontaneous acceptance after mouse liver allografting. (2008)
  • Author(s): Morita M
  • Organizer: 22^<th> International Congress of the Transplantation Society
  • Place of Presentation: Sydney
• [Presentation] Superagonist CD28 antibody preferentially expand Foxp3-expressing nTreg cells to prevent graft-versus-host disease. (2008)
  • Author(s): Kitazawa Y
  • Organizer: 22^<th> International Congress of the Transplantation Society
  • Place of Presentation: Sydney
• [Presentation] ラット骨髄由来間葉系幹細胞によるGvHD抑制効果についての検討 (2008)
  • Author(s): 北沢祐介
  • Organizer: 第44回日本移植学会総会
  • Place of Presentation: 大阪
• [Presentation] Superagonist CD28 antibody wcpand antigen-specific Foxp3-expressing nTreg cell to prevent graft-versus-host disease. (2008)
  • Author(s): Kitazawa Y
  • Organizer: 第38回日本移植学会総会
  • Place of Presentation: 京都
• [Presentation] CD28superagonistを用いた免疫寛容誘導 (2008)
  • Author(s): 李小康
  • Organizer: 第44回日本移植学会総会
  • Place of Presentation: 大阪