Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Blocking / adverse effects
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Antibodies, Monoclonal / adverse effects
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Antigens, Surface / biosynthesis
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Antigens, Surface / immunology
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Antigens, Surface / metabolism*
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Aorta / chemistry
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Aorta / cytology
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Aorta / metabolism
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Apoptosis Regulatory Proteins
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B7-1 Antigen / biosynthesis
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B7-1 Antigen / immunology
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B7-1 Antigen / metabolism*
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B7-H1 Antigen
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Cell Proliferation
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Cells, Cultured
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Coronary Disease / immunology*
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Coronary Disease / metabolism
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Cytokines / biosynthesis
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Graft Rejection / immunology*
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Graft Rejection / metabolism
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Heart Transplantation
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Interferon-gamma / immunology
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Lymphocyte Activation / immunology
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Male
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Membrane Glycoproteins / biosynthesis
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Membrane Glycoproteins / immunology
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Membrane Glycoproteins / metabolism*
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Mice
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Mice, Inbred C57BL
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Muscle, Smooth, Vascular / chemistry
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Muscle, Smooth, Vascular / cytology
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Muscle, Smooth, Vascular / metabolism
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Myocytes, Smooth Muscle / chemistry
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Myocytes, Smooth Muscle / metabolism
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Peptides / immunology
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Peptides / metabolism*
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Programmed Cell Death 1 Receptor
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T-Lymphocytes / metabolism
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T-Lymphocytes / physiology
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Transplantation, Homologous
Substances
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Antibodies, Blocking
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Antibodies, Monoclonal
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Antigens, Surface
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Apoptosis Regulatory Proteins
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B7-1 Antigen
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B7-H1 Antigen
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Cd274 protein, mouse
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Cytokines
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Membrane Glycoproteins
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Pdcd1 protein, mouse
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Peptides
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Programmed Cell Death 1 Receptor
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Interferon-gamma