2004 Fiscal Year Final Research Report Summary
Analysis of molecular mechanism of immunological rejection of transplanted heart and development of gene therapy for heart rejection
| Project/Area Number |
14370221
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Circulatory organs internal medicine
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
ISOBE Mitsuaki Tokyo Medical and Dental University, Department of Cardiovascular Medicine, Professor, 大学院・医歯学総合研究科, 教授 (80176263)
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| Co-Investigator(Kenkyū-buntansha) |
SUZUKI Jun-ichi Tokyo Medical and Dental University, Department of Cardiovascular Medicine, Lecturer, 医学部付属病院, 助手 (90313858)
AMANO Jun Shinshu University, Department of Surgery, Professor, 医学部, 教授 (20138283)
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| Project Period (FY) |
2002 – 2004
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| Keywords | heart transplantation / organ rejection / transplantation immunology / hepatocyte growth factor / PD-1 / HVEM / tolerance / T cell |
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| Research Abstract |
Cardiac allograft rejection is still a major complication after heart transplantation. This project was aimed to develop novel gene therapies for preventing acute and chronic rejection of cardiac allograft. The TNF superfamily member LIGHT, which binds herpes virus entry mediator (HVEM) and lymphotoxin _receptor (LT_R), plays important roles in regulating the immune response. To clarify the mechanism underlying graft arterial disease (GAD), we investigated the role of the LIGHT pathway in the progression of GAD. We showed that the LIGHT pathway plays important roles in the regulation not only of T cell activation but also of SMC proliferation using mouse model of heart transplantation. Blockade of the LIGHT pathway is a promising avenue for the prevention of GAD. Programmed death 1 (PD-1), a member of the CD28 family, is involved in the negative regulation of the immune response and plays a particularly important role in the regulation of peripheral tolerance. Programmed death-ligand 1
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(PD-L1) expression has been detected in lymphoid as well as non-lymphoid organs. We investigated the role of the PD-1/PD-L1 pathway in acute and chronic rejection in murine cardiac transplantation models. Administration of anti-PD-L1 mAb significantly accelerated allograft rejection in a fully allogeneic model. Immunohistochemistry showed significantly increased numbers of infiltrating cells. In a class II mismatch model, PD-L1 was expressed in smooth muscle cells (SMCs) of the thickened intima in the graft coronary artery, and the administration of anti-PD-L1 mAb enhanced the progression of GAD. The PD-1/PD-L1 pathway regulates both acute and chronic rejection in cardiac transplantation. Thus, control of this pathway should provide a potent strategy for improving graft survival and suppressing GAD. Hepatocyte growth factor (HGF) is a pleiotropic factor that plays an important role in tissue repair and regeneration. We show the effect of HGF on acute cardiac rejection and assess its immunomodulative role. HGF treatment resulted in a significant prolongation in graft survival, and tolerance was induced in 40% of the recipients. In HGF-treated allografts, the expression of interferon-_mRNA was decreased, and the expressions of interleukin-10 and transforming growth factor-_1 mRNA were enhanced. Our findings suggest that HGF could modify the alloimmuno response mediated by T helper cells. Thus, HGF administration could constitute a new therapeutic approach for prevention of acute rejection in patients undergoing cardiac transplantation. The goal of this project is to develop clinical application of gene therapy for minimizing acute and chronic rejection. We evaluated the utility of the NF-kB decoy for preventing restenosis after PCI. We started clinical trials. An initial case was suffering from effort angina with stenosis in the middle (#2) portions of the right coronary artery. He received stents ; we delivered the NF-kB decoy at the distal site (#2) and no decoy at the proximal site (#1). Six months after the PCI, NF-kB decoy suppressed the restenosis compared to no decoy transfection. No systemic adverse effects were observed. This suggests the clinical safety of NF-kB decoy for preventing heart disease. Thus, we showed that these methods could be applied to prevent graft failure without systemic adverse effects. Less
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[Journal Article] Suppression of acute and chronic rejection by hepatocyte growth factor in a murine model of cardiac transplantation : Induction of tolerance and prevention of cardiac allograft vasculopathy.2004
Author(s)
Yamaura K, Ito K, Tsukioka K, Wada Y, Makiuchi A, Sakaguchi M, Akashima T, Fujimori M, Sawa Y, Morishita R, Matsumoto K, Nakamura T, Suzuki J, Amano J, Isobe M
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Journal Title
Circulation 110
Pages: 1650-1657
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] The Blockade of the Interaction Between Programmed Death-1 (PD-1) and Its Ligand PD-L1 Accelerates Graft Arterial Disease (GAD) in Cardiac Allografts.2004
Author(s)
Koga N, Suzuki J, Kosuge H, Haraguchi G, Onai Y, Futamatsu H, Gotoh R, Saiki H, Tsushima F, Azuma M, *Isobe M
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Journal Title
Arterioscler Throm Vasc Biol 24
Pages: 2057-2062
Description
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[Journal Article] Intimal hyperplasia in cardiac allografts is dependent upon transcriptional regulator Egr-1 : effective inhibition by antisense Egr-1 ODN transfection.2003
Author(s)
Wada Y, Fujimori M, Suzuki J, Kawauchi M, Tsukioka K, Sawa Y, Morishita R, Kaneda Y, Takamoto S, Isobe M, Amano J
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Journal Title
J Surg Res 115
Pages: 294-302
Description
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[Journal Article] Adenovirus vector containing CTLA4IgG induces clinically relevant immunosuppression via Cre/LoxP-mediated gene recombination.
Author(s)
Izawa A, Sano K, Takehara M, Inobe M, Suzki J, Oka T, Imamura H, Kubo K, Takahashi M, Ikeda U, Amano J, *Isobe M, Uede T
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