Background-Programmed death-1 (PD-1), a member of the CD28 family, has been identified. PD-1 is involved in the negative regulation of some immune responses. We evaluated the role of PD-ligand 1 (PD-L1) in graft arterial disease (GAD) of cardiac allografts and in smooth muscle cells (SMCs). Methods and Results-C57BL/6 murine hearts were transplanted into B6.C-H2Ͻbm12ϾKhEg mice for examination of GAD. PD-L1 was expressed in SMCs of the thickened intima in the graft coronary arteries, and administration of anti-PD-L1 monoclonal antibody (mAb) enhanced the progression of GAD (luminal occlusion: 55Ϯ5.0% versus 9.8Ϯ4.3%, PϽ0.05). The expressions of interferon ␥ (IFN-␥) and tumor necrosis factor ␣ of cardiac allografts were upregulated in response to anti-PD-L1 mAb treatment. In vitro, PD-L1 expression was induced in SMCs in response to IFN-␥ stimulation. Sensitized splenocytes increased SMC proliferation, and anti-PD-L1 mAb in combination with IFN-␥ stimulation increased this proliferation. Key Words: transplantation Ⅲ graft arterial disease Ⅲ smooth muscle cell Ⅲ immune system Ⅲ B7 family C ardiac allograft transplantation developed as a therapy for end-stage congestive heart failure. The survival rate at 1 year after transplantation has increased to Ͼ80% by introduction of immunosuppressive drugs. 1 However, the use of the drugs also results in opportunistic infection, and these drugs do not prevent graft arterial disease (GAD), which occurs in chronic rejection. Conclusions-TheProgrammed death-1 (PD-1) is a member of the CD28 family that was identified in a T cell line undergoing programmed cell death, 2 but subsequent studies have shown that its expression is associated with lymphocyte activation rather than cell death. 3,4 PD-1 contains an immunoreceptor tyrosine-based inhibitory motif in its cytoplasmic tail. 5 C57BL/6 mice lacking PD-1 develop lupus-like arthritis and glomerulonephritis, 6 and Balb/c mice lacking PD-1 develop fatal dilated cardiomyopathy. 7 Okazaki et al purified the 30-kDa protein from heart extract and identified it as cardiac troponin I in these dilated cardiomyopathy mice, and administration of anti-cardiac troponin I (anti-cTnI) antibody induced heart dilation and dysfunction in wild-type mice. 8 The data suggest that PD-1 receptor engagement leads to downregulation of immune responses. Furthermore, PDligand 1 (PD-L1) was recently identified. 9 PD-1 ligand shows a tissue distribution profile distinct from that of the other B7 family members. Expression of PD-L1 is upregulated on activation of antigen presenting cells, including dendritic cells, monocytes, and B cells. In addition, PD-L1 has been detected in lymphoid as well as in nonlymphoid organs. 10,11 Although Ozkaynak et al reported the expressions and functional roles of PD-1 and PD-L1 in the pathogenesis of cardiac transplants, 12 the relation between the PD-1/PD-L1 pathway and the proliferation of smooth muscle cells (SMCs) has not been investigated. In the present study, we examined the expression of PD-1 and PD-L1 in relation to...

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Pitavastatin could be effective in the suppression of acute rejection and GAD development in cardiac transplantation.

SUMMARY4-1BB, 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-γ , 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. (Int Heart J 2008; 49: 105-118)