Yang Junbao, Jaramillo Andrés, Liu Wei, Olack Barbara, Yoshimura Yoshitaka, Joyce Sebastian, Kaleem Zahid, Mohanakumar T
Department of Surgery, Washington University School of Medicine, St Louis, MO 63110-1093, USA.
Transplantation. 2003 Jul 15;76(1):84-91. doi: 10.1097/01.TP.0000072013.21336.64.
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.
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.
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.
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.
次要组织相容性抗原（mHag）不匹配已被证明在骨髓移植后的移植物抗宿主病中起关键作用。然而，mHag在实体器官同种异体移植排斥反应中的作用仍不清楚。因此，本研究的目的是确定源自多态性H13等位基因的单个mHag不匹配在小鼠心脏同种异体移植排斥反应发生发展中的作用。H13a和H13b等位基因分别编码与H2Db分子结合的SSVVGVWYL（SVL9）和SSVIGVWYL（SIL9）mHag。
将C56BL/10SnJ（H13a）心脏同种异体移植到同基因的B10.CE-H13b Aw(30NX)/Sn（H13b）小鼠体内。每天监测同种异体移植功能，心跳停止定义为排斥反应。通过组织学检查确认排斥反应。分别通过用H13a特异性四聚体进行原位和体外染色以及铬-51（51Cr）释放试验分析移植浸润细胞的表型和功能特征。
65%的H13不相容同种异体移植在37.0±14.5天被排斥。移植到H13a致敏小鼠体内的68%的H13a同种异体移植排斥更早，在27.6±15.9天被排斥。被排斥的同种异体移植表现出慢性排斥的组织病理学迹象，伴有弥漫性单核细胞浸润、同心性内膜增生和纤维化。在被排斥的同种异体移植中观察到CD8+（87%）和CD4+（13%）T细胞。此外，60%的移植浸润CD8+ T细胞识别H2Db/SVL9四聚体。移植浸润CD8+ T细胞表现出显著的H2Db限制性、SVL9特异性细胞毒性活性。
如H13差异所示，单个mHag不匹配导致主要组织相容性复合体匹配的血管化实体器官同种异体移植慢性排斥的发病机制。
