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.

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 H13 a and H13 b alleles encode for the SSVVGVWYL (SVL9) and SSVIGVWYL (SIL9) mHag bound to the H2D b molecule, respectively. Methods. C56BL/10SnJ (H13 a ) cardiac allografts were transplanted into congenic B10.CE-H13 b A w (30NX)/Sn (H13 b ) 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 H13 a -specific tetramers and by chromium-51 ( 51 Cr)-release assay, respectively. Results. Sixty-five percent of H13-incompatible allografts were rejected in 37.0±14.5 days. Sixty-eight percent of the H13 a allografts transplanted into H13 a -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 H2D b /SVL9 tetramer. Graft-infiltrating CD8 + T cells showed a significant H2D b -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.