Blockade of the Interaction Between PD-1 and PD-L1 Accelerates Graft Arterial Disease in Cardiac Allografts

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-H2KhEg 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: 55+/-5.0% versus 9.8+/-4.3%, P<0.05). The expressions of interferon gamma (IFN-gamma) and tumor necrosis factor alpha 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-gamma stimulation. Sensitized splenocytes increased SMC proliferation, and anti-PD-L1 mAb in combination with IFN-gamma stimulation increased this proliferation. CONCLUSIONS: The PD-L1 pathway regulates both the proliferation of SMCs and GAD. Thus, control of this interaction is a promising strategy for suppression of GAD.