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-H2 < bm12 > KhEg 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.