Published online before print September 16, 2004, doi: 10.1161/01.ATV.0000145015.23656.e4
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© 2004 American Heart Association, Inc.
Vascular Biology |
Blockade of the Interaction Between PD-1 and PD-L1 Accelerates Graft Arterial Disease in Cardiac Allografts
From the Departments of Cardiovascular Medicine (N.K, J.S., H.K., G.H., Y.O., H.F., Y.M., R.G., H.S., M.I) and Molecular Immunology (F.T., M.A.), Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
Correspondence to Mitsuaki Isobe, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail isobemi.cvm{at}tmd.ac.jp
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 
(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.
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.
Programmed death 1 (PD-1) is involved in the negative regulation of immune responses. We evaluated the role of PD-ligand 1 (PD-L1) in graft arterial disease (GAD) of cardiac allografts. PD-L1 was expressed in smooth muscle cells of the thickened intima, and anti–PD-L1 monoclonal antibody enhanced the progression of GAD. In vitro, sensitized splenocytes increased smooth muscle cell proliferation, and anti–PD-L1 monoclonal antibody increased this proliferation. The PD-L1 pathway regulates GAD. Thus, control of this interaction is a promising strategy for suppression of GAD.
Key Words: transplantation • graft arterial disease • smooth muscle cell • immune system • B7 family
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