Blockade of the 4-1BB Pathway Attenuates Graft Arterial Disease in Cardiac Allografts

• Saiki Hitoshi

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Suzuki Jun-ichi

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Kosuge Hisanori

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Haraguchi Go

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Ishihara Takashi

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Haga Takaaki

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Maejima Yasuhiro

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Isobe Mitsuaki

  Department of Cardiovascular Medicine, Tokyo Medical and Dental University

• Uede Toshimitsu

  Division of Molecular Immunology, Institute for Genetic Medicine, Hokkaido University

Abstract

4-1BB, a member of the tumor necrosis factor (TNF) receptor superfamily, binds the 4-1BB ligand (4-1BBL) and works as a costimulatory molecule and regulates T cell-mediated immune responses. Because T cell-mediated immunity is associated with graft arterial disease (GAD), we investigated the role of the 4-1BB pathway in the progression of GAD.<br> Hearts from C57BL/6 mice were transplanted into Bm12 mice (class II mismatch). 4-1BB expression was induced on CD4⁺ and CD8⁺ splenocytes in allografts after cardiac transplantation. 4-1BBL was detected in the vessel wall of the rejecting cardiac allograft and in cultured smooth muscle cells (SMCs) stimulated with fetal calf serum. Recipients were injected intraperitoneally with 4-1BBIg every 7 days for 8 weeks. GAD was significantly attenuated by 4-1BBIg treatment (luminal occlusion, 15.4 ± 3.1% versus control IgG treatment, 75.6 ± 4.6%, P < 0.001). T-cell infiltration of cardiac allografts and expression of interferon-g , interleukin-6, and interleukin-15 in cardiac allografts were suppressed by 4-1BBIg treatment. Coculture of SMCs with sensitized splenocytes after transplantation induced SMC proliferation, and this was inhibited by addition of 4-1BBIg.<br> The 4-1BB pathway regulates not only T-cell activation but also SMC proliferation. Blockade of the 4-1BB pathway is a promising strategy to prevent progression of GAD. <br>

Journal

• International Heart Journal

  International Heart Journal 49 (1), 105-118, 2008

  International Heart Journal Association

Keywords

• Atherosclerosis
• Immune system
• Transplantation
• Costimulatory molecules
• Smooth muscle cells

Details

• CRID: 1390001205224679296
• NII Article ID: 130000068976
• DOI: 10.1536/ihj.49.105
• ISSN: 13493299
• ISSN: 13492365
• Web Site: http://www.jstage.jst.go.jp/article/ihj/49/1/49_1_105/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2008230098
• Text Lang: en
• Data Source:
  • JaLC
  • Crossref
  • CiNii Articles
• Abstract License Flag: Disallowed