The induction of donor-specific tolerance in experimental renal allo-transplantation

尽管目前临床器官移植的免疫抑制治疗已经提高了同种异体移植物的存活率，但长期给药的治疗相关并发症仍然是长期成功的主要限制因素。因此，临床器官移植的主要目标是诱导供者特异性移植耐受。然而，移植耐受的机制仍不完全清楚。(1)我们研究阐明了在耐受诱导方案中与耐受发展相关的肾移植物内事件，并且我们表明在耐受发展过程中肾移植物中发生T细胞无反应性和T细胞缺失。(2)我们检查了与本方案中耐受诱导失败相关的同种异体肾移植物的特征，我们还指出，在耐受诱导方案中，不稳定的耐受诱导与介导免疫抑制的持续免疫激活有关。 ...更多信息 急性和/或慢性排斥反应中移植物实质细胞的逻辑破坏。(3)我们研究了慢性排斥反应的发展过程，因为晚期肾移植失败的主要原因是慢性排斥反应，但对其发病机制知之甚少。病理学上，慢性排斥反应的特征是进行性间质纤维化、肾小管萎缩、慢性移植物肾小球病和慢性移植物动脉病。针对PTC和肾小管的持续性排斥反应以及肌成纤维细胞的增殖是慢性排斥反应进行性间质纤维化的显著特征，可能是其发病机制中的关键事件。针对肾小球和动脉内皮细胞的急性和持续的细胞和抗体介导的排斥反应是急性移植物肾小球病和急性动脉内膜炎以及进展为慢性移植物肾小球病和慢性移植物动脉病的关键致病决定因素。其可以诱导对移植器官的特异性免疫无应答性而不需要长期施用免疫抑制剂移植在耐受诱导方案中，快速稳定的耐受诱导对于长期稳定的移植物接受是必要的。少

Although current immunosuppressive therapy for clinical organ transplantation has improved allograft survival, treatment-related complications of chronic drug administration still remain a major limitation to long-term success. Therefore, the major goal of clinical organ transplantation is to induce donor-specific transplantation tolerance. However, the mechanism of transplantation tolerance is still incompletely understood. (1) We examined to clarify the intra-renal allograft events associated with the development of tolerance in the tolerance induction protocol, and we indicated that both T cell anergy and T cell deletion occurred in the renal allografts during the development of tolerance. (2) We examined the characterization of renal allografts associated with the failure of tolerance induction in this protocol, and we also indicated that, in tolerance induction protocols, unstable tolerance induction was associated with the persistent immunological activation that mediated immunol … More ogical destruction of graft parenchymal cells in acute and/or chronic rejection. (3) We examined the process of the development of chronic rejection, because the leading cause of late kidney allograft failure is chronic rejection, yet little is known about its pathogenesis. Pathologically, chronic rejection was characterized by progressive interstitial fibrosis, tubular atrophy, chronic allograft glomerulopathy, and chronic allograft arteriopathy. The persistent rejection directed at PTCs and tubules, and proliferation of myofibroblasts were prominent features in the progressive interstitial fibrosis in chronic rejection, and were probably key events in its pathogenesis. The acute and persistent cell- and antibody-mediated rejection against glomerular and arterial endothelial cells was key pathogenic determinant of acute allograft glomerulopathy and acute endarteritis as well as progression to chronic allograft glomerulopathy and chronic allograft arteriopathy.We conclude that several strategies of active tolerance induction, which can induce specific immunologic unresponsiveness to the transplanted organ without prolonged administration of immunosuppressive agents is important in the organ transplantation. In treatment with tolerant induction protocol, rapid and stable tolerance induction is necessary for long term stable graft acceptance. Less