title: Pig to rat cell transplantation: reduced cellular and antibody responses to xenografts overexpressing PD-L1.
abstract: BACKGROUND
  Programmed death-1 (PD-1) costimulation acts as a negative regulator of T-cell responses to allografts. However, the role of the PD-1 pathway in xenotransplantation is not well defined yet. We have shown previously that human in vitro T-cell responses to porcine transfectants overexpressing PD-Ligand1 (L23-PD-L1 cells) are remarkably weak. In this report, we asked whether the PD-1/PD-L1 pathway has the potential to diminish xenogeneic immune responses also in vivo.
  
  
  METHODS
  L23-PD-L1 or mock transfected control cells (L23-GFP) were transplanted under the kidney capsule of rats. The occurrence of kidney-infiltrating rat leukocytes and the induction of anti-pig antibodies were monitored in grafted animals.
  
  
  RESULTS
  Assessment of cellular infiltrates revealed similar numbers of macrophages in kidneys grafted with L23-PD-L1 or L23-GFP control cells. However, the level of MHC class-II molecules was reduced on macrophages responding to L23-PD-L1 grafts, suggesting a lower state of activation. Furthermore, less T cells were found in kidneys receiving L23-PD-L1 cells. In addition, the titers of induced anti-pig antibodies were significantly lower in rats grafted with L23-PD-L1 cells.
  
  
  CONCLUSIONS
  These data suggest that signals triggered by PD-1-PD-L1 interaction interfere with activation pathways involved in the induction of cellular and antibody-mediated immune responses to xenografts in vivo. Targeting of PD-1 and/or PD-L1 may be a promising approach for immune modulation after xenotransplantation.
authors.affiliation: Transplant Laboratory, Department of General-, Visceral-, and Transplantation Surgery, Hannover Medical School, Hannover, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Plege-Fleck
authors.forename: Thorsten
authors.initials: T
authors.lastname: Lieke
authors.forename: Dorothee
authors.initials: D
authors.lastname: Römermann
authors.forename: Heike
authors.initials: H
authors.lastname: Düvel
authors.forename: Joachim
authors.initials: J
authors.lastname: Hundrieser
authors.forename: Anna
authors.initials: A
authors.lastname: Buermann
authors.forename: Lilli
authors.initials: L
authors.lastname: Kraus
authors.forename: Jürgen
authors.initials: J
authors.lastname: Klempnauer
authors.forename: Reinhard
authors.initials: R
authors.lastname: Schwinzer
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology*; D060890:B7-H1 Antigen / Q000276:immunology* / Q000378:metabolism; D002469:Cell Separation / Q000379:methods; D017690:Cell Transplantation / Q000379:methods; D006084:Graft Rejection / Q000276:immunology* / Q000378:metabolism; D064593:Heterografts / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D051381:Rats; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous / Q000379:methods
chemical_list: D060890:B7-H1 Antigen
keywords: PD-1/PD-Ligands; immune modulation; negative costimulation