on September 16, 2004
Published online before print September 16, 2004, doi: 10.1161/01.ATV.0000145015.23656.e4
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Submitted on May 31, 2004
Accepted on August 23, 2004
Blockade of the Interaction Between PD-1 and PD-L1 Accelerates Graft Arterial Disease in Cardiac Allografts
Noritaka Koga ;
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.
* To whom correspondence should be addressed. 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.
Key words: transplantation • graft arterial disease • smooth muscle cell • immune system • B7 family
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