title: Chronic rejection of murine cardiac allografts discordant at the H13 minor histocompatibility antigen correlates with the generation of the H13-specific CD8+ cytotoxic T cells.
abstract: BACKGROUND
  Minor histocompatibility antigen (mHag) discordances have been shown to play a critical role in graft-versus-host disease after bone marrow transplantation. However, the role of mHag in rejection of solid-organ allografts remains unknown. Therefore, the goal of this study was to define the role of a single mHag discordance derived from the polymorphic H13 allele in the development of cardiac allograft rejection in mice. The H13a and H13b alleles encode for the SSVVGVWYL (SVL9) and SSVIGVWYL (SIL9) mHag bound to the H2Db molecule, respectively.
  
  
  METHODS
  C56BL/10SnJ (H13a) cardiac allografts were transplanted into congenic B10.CE-H13b Aw(30NX)/Sn (H13b) mice. Allograft function was monitored daily and rejection was defined by cessation of heart beat. Rejection was confirmed histologically. The phenotypic and functional characteristics of the graft-infiltrating cells were analyzed by in situ and in vitro staining with H13a-specific tetramers and by chromium-51 (51Cr)-release assay, respectively.
  
  
  RESULTS
  Sixty-five percent of H13-incompatible allografts were rejected in 37.0+/-14.5 days. Sixty-eight percent of the H13a allografts transplanted into H13a-sensitized mice were rejected earlier, in 27.6+/-15.9 days. Rejected allografts showed histopathologic signs of chronic rejection with diffuse mononuclear cell infiltration, concentric intimal hyperplasia, and fibrosis. Both CD8+ (87%) and CD4+ (13%) T cells were observed in rejected allografts. In addition, 60% of the graft-infiltrating CD8+ T cells recognized a H2Db/SVL9 tetramer. Graft-infiltrating CD8+ T cells showed a significant H2Db-restricted, SVL9-specific cytotoxic activity.
  
  
  CONCLUSIONS
  A single mHag discordance, as demonstrated with H13 disparity, results in the pathogenesis of chronic rejection of major histocompatibility complex-matched vascularized solid-organ allograft.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St Louis, MO 63110-1093, USA.
authors.forename: Junbao
authors.initials: J
authors.lastname: Yang
authors.forename: Andrés
authors.initials: A
authors.lastname: Jaramillo
authors.forename: Wei
authors.initials: W
authors.lastname: Liu
authors.forename: Barbara
authors.initials: B
authors.lastname: Olack
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Yoshimura
authors.forename: Sebastian
authors.initials: S
authors.lastname: Joyce
authors.forename: Zahid
authors.initials: Z
authors.lastname: Kaleem
authors.forename: T
authors.initials: T
authors.lastname: Mohanakumar
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D004195:Disease Models, Animal; D005786:Gene Expression Regulation / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D016027:Heart Transplantation / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000235:genetics; D007378:Interleukins / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D008815:Mice, Inbred Strains; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D008912:Minor Histocompatibility Loci; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000473:pathology; D014184:Transplantation, Homologous / Q000276:immunology; D014185:Transplantation, Isogeneic / Q000276:immunology
chemical_list: C108856:H13 protein, mouse; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D007371:Interferon-gamma