title: Prolongation of skin graft survival by modulation of the alloimmune response with alternatively activated dendritic cells.
abstract: BACKGROUND
  Activation of immature dendritic cells (DC) in the presence of the glucocorticoid hormone dexamethasone (DEX) results in alternatively matured DC that present antigen in the absence of a proper co-stimulatory context. This maturation process is irreversible, making these cells an attractive potential tool for the induction of antigen-specific T-cell tolerance in vivo. The authors explored the possibility of using these DC for the induction of transplantation tolerance in a fully allogeneic setting in mice.
  
  
  METHODS
  Immature dendritic cells (D1, an immature splenic DC line derived from B6 mice) were pretreated with DEX for 24 hr, after which lipopolysaccharide or nothing was added to the culture for another 48 hr. These cells were analyzed for their in vitro and in vivo stimulating or tolerizing capacities.
  
  
  RESULTS
  In line with their phenotype, including decreased interleukin (IL)-12 production, in vitro co-culture of alternatively matured D1 (B6 origin; H-2b) with completely allogeneic T cells of BALB/c origin led to a significant decrease in the alloreactive T-cell response. A single injection of 1 x 10(6) alternatively matured H-2b DC into BALB/c mice induced a different alloimmune response compared with mature DC. The responding T cells showed a lower proliferation rate and a lower interferon-gamma production, whereas a significantly higher proportion of the cells produced IL-10 as measured ex vivo by enzyme-linked immunospot assay. Furthermore, injection with alternatively matured DC, followed by transplantation of fully mismatched skin grafts (C57BL/6), led to a significantly prolonged survival compared with that of mature DC-pretreated mice or untreated mice. The immunomodulatory effect was antigen specific, as third-party reactive alloresponses were not affected.
  
  
  CONCLUSIONS
  The authors' data constitute the first direct demonstration that DC alternatively matured in the presence of glucocorticoid hormones can be exploited for the specific suppression of the alloreactive Th1 response, resulting in a delayed skin graft rejection in a complete major histocompatibility complex-incompatible strain combination.
authors.affiliation: Department of Immunohematology and Blood Transfusion, Leiden University Medical Center, Leiden, The Netherlands. d.l.roelen@lumc.nl
authors.forename: Dave L
authors.initials: DL
authors.lastname: Roelen
authors.forename: Danita H
authors.initials: DH
authors.lastname: Schuurhuis
authors.forename: Daniëlle E M
authors.initials: DE
authors.lastname: van den Boogaardt
authors.forename: Karin
authors.initials: K
authors.lastname: Koekkoek
authors.forename: Paula P M C
authors.initials: PP
authors.lastname: van Miert
authors.forename: Jolien J
authors.initials: JJ
authors.lastname: van Schip
authors.forename: Sandra
authors.initials: S
authors.lastname: Laban
authors.forename: Delphine
authors.initials: D
authors.lastname: Rea
authors.forename: Cees J M
authors.initials: CJ
authors.lastname: Melief
authors.forename: Rienk
authors.initials: R
authors.lastname: Offringa
authors.forename: Ferry
authors.initials: F
authors.lastname: Ossendorp
authors.forename: Frans H J
authors.initials: FH
authors.lastname: Claas
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology* / Q000637:transplantation*; D003907:Dexamethasone / Q000494:pharmacology; D005260:Female; D005434:Flow Cytometry; D006085:Graft Survival / Q000502:physiology*; D007165:Immunosuppression Therapy / Q000379:methods; D008070:Lipopolysaccharides / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D008808:Mice, Inbred CBA; D016038:Skin Transplantation / Q000276:immunology / Q000502:physiology*; D014184:Transplantation, Homologous / Q000276:immunology
chemical_list: D008070:Lipopolysaccharides; D003907:Dexamethasone