title: Absence of donor MHC antigen expression ameliorates chronic kidney allograft rejection.
abstract: BACKGROUND
  In previous studies, we have demonstrated that a subset of mouse kidney allografts has prolonged survival without any immunosuppressive treatment. Chronic rejection (CR) develops in these long surviving grafts. The pathologic features of CR in this model are similar to CR in human kidney grafts.
  
  
  METHODS
  To explore the role of donor major histocompatibility complex (MHC) antigens in the development of CR, we performed vascularized kidney transplants using kidneys from donor mice that lack expression of both MHC class I and II antigens (MHC-/-).
  
  
  RESULTS
  Survival was significantly improved in recipients of MHC-/- allografts. This enhanced survival was associated with higher glomerular filtration rate (GFR) in MHC-/- allografts (4.92 +/- 0.54 cc/min/kg) compared to controls (2.19 +/- 0.63 cc/min/kg; P = 0.004). The typical histologic features of CR were markedly reduced in MHC-/- allografts. Semiquantitative histopathological scores for MHC-/- grafts (13.3 +/- 2.1) were significantly lower than in control allografts (19.0 +/- 1.0; P = 0.04). Along with this improvement in structural abnormalities, significantly fewer CD4+ T (38.3 cells/mm(2) vs. 75.0 cells/mm(2); P = 0.008), CD8+ T cells (38.7 vs. 96 cells/mm(2), respectively; P = 0.008) and macrophages (60 vs. 134 cells/mm(2), respectively; P = 0.04) infiltrated MHC-/- allografts compared to controls. The levels of intragraft cytokine mRNA expression also were reduced in MHC-/- allografts compared to control allografts. Finally, serum alloantibodies were virtually undetectable in recipients of MHC-/- kidney allografts.
  
  
  CONCLUSIONS
  Cell surface expression of donor MHC antigens promotes the development of CR. Donor antigen expression promotes the accumulation of infiltrating cells in the graft and the development of donor specific alloantibodies. Abrogation of these responses is associated with improved graft survival and reduced CR in MHC-/- grafts.
authors.affiliation: Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, Durham, North Carolina, USA.
authors.forename: Roslyn B
authors.initials: RB
authors.lastname: Mannon
authors.forename: Robert
authors.initials: R
authors.lastname: Griffiths
authors.forename: Phillip
authors.initials: P
authors.lastname: Ruiz
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Platt
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Coffman
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D006084:Graft Rejection / Q000209:etiology*; D006085:Graft Survival; D006649:Histocompatibility Antigens / Q000502:physiology*; D007518:Isoantibodies / Q000096:biosynthesis; D007668:Kidney / Q000473:pathology; D016030:Kidney Transplantation / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D006649:Histocompatibility Antigens; D007518:Isoantibodies; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta