title: Critical role of donor tissue expression of programmed death ligand-1 in regulating cardiac allograft rejection and vasculopathy.
abstract: BACKGROUND
  Allograft vasculopathy is a major limiting factor in the long-term success of cardiac transplantation. T cells play a critical role in initiation of cardiac allograft rejection and allograft vasculopathy. The negative T-cell costimulatory pathway PD-1:PDL1/PDL2 (programmed death-1:programmed death ligand-1/2) plays an important role in regulating alloimmune responses. We investigated the role of recipient versus donor PD-1 ligands in the pathogenesis of allograft rejection with emphasis on the role of tissue expression in regulating this alloimmune response in vivo.
  
  
  RESULTS
  We used established major histocompatibility complex class II- and class I-mismatched models of vascularized cardiac allograft rejection, blocking anti-PDL1 and anti-PDL2 antibodies, and PDL1- and PDL2-deficient mice (as donors or recipients) to study the role of the PD-1:PDL1/PDL2 pathway in chronic rejection. We also used PDL1-deficient and wild-type mice and bone marrow transplantation to generate chimeric animals that express PDL1 exclusively on either hematopoietic or parenchymal cells. PDL1 but not PDL2 blockade significantly accelerated cardiac allograft rejection in the bm12-into-B6 and B6-into-bm12 models. Although wild-type cardiac allografts survived long term, PDL1-/- donor hearts transplanted into wild-type bm12 mice exhibited accelerated rejection and vasculopathy associated with enhanced recipient T-cell alloreactivity. Interestingly, PDL1-/- recipients did not exhibit an accelerated tempo of cardiac allograft rejection. Using chimeric animals as donors, we show that PDL1 expression on cardiac tissue alone significantly prolonged graft survival compared with full PDL1-/- donor grafts in transplanted wild-type recipients.
  
  
  CONCLUSIONS
  This is the first report to demonstrate that expression of the negative costimulatory molecule PDL1 on donor cardiac tissue regulates recipient alloimmune responses, allograft rejection, and vasculopathy.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, 221 Longwood Ave, Boston, MA 02115, USA.
authors.forename: Jun
authors.initials: J
authors.lastname: Yang
authors.forename: Joyce
authors.initials: J
authors.lastname: Popoola
authors.forename: Shakila
authors.initials: S
authors.lastname: Khandwala
authors.forename: Nidyanandh
authors.initials: N
authors.lastname: Vadivel
authors.forename: Vijay
authors.initials: V
authors.lastname: Vanguri
authors.forename: Xueli
authors.initials: X
authors.lastname: Yuan
authors.forename: Shirine
authors.initials: S
authors.lastname: Dada
authors.forename: Indira
authors.initials: I
authors.lastname: Guleria
authors.forename: Chaorui
authors.initials: C
authors.lastname: Tian
authors.forename: M Javeed
authors.initials: MJ
authors.lastname: Ansari
authors.forename: Tahiro
authors.initials: T
authors.lastname: Shin
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Miyuki
authors.initials: M
authors.lastname: Azuma
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
authors.forename: Anil
authors.initials: A
authors.lastname: Chandraker
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000235:genetics*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000235:genetics*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology; D006650:Histocompatibility Testing; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D061026:Programmed Cell Death 1 Receptor; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; D000949:Histocompatibility Antigens Class II; C491383:Pdcd1 protein, mouse; C484279:Pdcd2 protein, mouse; D061026:Programmed Cell Death 1 Receptor