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  • Title: Blockade of the 4-1BB pathway attenuates graft arterial disease in cardiac allografts.
    Author: Saiki H, Suzuki J, Kosuge H, Haraguchi G, Ishihara T, Haga T, Maejima Y, Isobe M, Uede T.
    Journal: Int Heart J; 2008 Jan; 49(1):105-18. PubMed ID: 18360069.
    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. 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. 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.
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