title: Blockade of the interaction between PD-1 and PD-L1 accelerates graft arterial disease in cardiac allografts.
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).
  
  
  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.
authors.affiliation: Department of Cardiovascular Medicine, Tokyo Medical and Dental University, Tokyo, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Koga
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Suzuki
authors.forename: Hisanori
authors.initials: H
authors.lastname: Kosuge
authors.forename: Go
authors.initials: G
authors.lastname: Haraguchi
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Onai
authors.forename: Hideki
authors.initials: H
authors.lastname: Futamatsu
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Maejima
authors.forename: Ryo
authors.initials: R
authors.lastname: Gotoh
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Saiki
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Tsushima
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Isobe
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000009:adverse effects; D000954:Antigens, Surface / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D001011:Aorta / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D060890:B7-H1 Antigen; D049109:Cell Proliferation; D002478:Cells, Cultured; D003327:Coronary Disease / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D016027:Heart Transplantation; D007371:Interferon-gamma / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009131:Muscle, Smooth, Vascular / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000737:chemistry / Q000378:metabolism; D010455:Peptides / Q000276:immunology / Q000378:metabolism*; D061026:Programmed Cell Death 1 Receptor; D013601:T-Lymphocytes / Q000378:metabolism / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D019138:Antibodies, Blocking; D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D018122:B7-1 Antigen; D060890:B7-H1 Antigen; C498919:Cd274 protein, mouse; D016207:Cytokines; D008562:Membrane Glycoproteins; C491383:Pdcd1 protein, mouse; D010455:Peptides; D061026:Programmed Cell Death 1 Receptor; D007371:Interferon-gamma