Afrouzian Marjan, Ramassar Vido, Urmson Joan, Zhu Lin-Fu, Halloran Philip F
Department of Medicine, Division of Nephrology and Immunology, and Department of Surgery, University of Alberta, Edmonton, Alberta, Canada.
J Am Soc Nephrol. 2002 May;13(5):1199-209. doi: 10.1097/01.asn.0000013302.11876.a5.
In many circumstances kidney transplants remain viable despite extensive inflammation, permitting rejection episodes to be reversed. The mechanisms by which the kidney resists host effector mechanisms are not known. In mouse kidney transplants, resistance requires interferon-gamma (IFN-gamma), which acts on the graft to protect the graft from necrosis during the first days of rejection as well as inducing major histocompatibility complex (MHC) expression. Because some effects of IFN-gamma are mediated by transcription factor IRF-1, the role of IRF-1 in the donor tissue early phases of rejection of mouse kidney allografts was studied. H-2(b) kidneys were transplanted from mice with wild-type IRF-1 genes (WT) or mice with disrupted IRF-1 genes (IRF-1KO) into CBA (H-2(k)) recipients. At day 5 and day 7, IRF-1KO and WT kidneys were functioning despite typical rejection pathology: interstitial infiltration and tubulitis. However, function deteriorated rapidly in rejecting IRF-1KO allografts, associated with widespread epithelial necrosis, peritubular capillary congestion, glomerulitis, and fibrin thrombi in small veins by day 7. At day 21, WT kidneys were viable despite severe tubulitis and arteritis, whereas IRF-1KO kidneys showed massive necrosis of the epithelium despite patent large vessels. Compared with WT kidneys, rejecting IRF-1KO kidneys showed less induction of donor MHC yet had similar mRNA levels of perforin, granzyme B, and Fas ligand and evoked host alloantibody responses. Thus in rejecting kidney transplants, IRF-1 in the graft mediates MHC induction, but it also mediates resistance to necrosis, an effect that could be crucial to permit success in interventions against rejection.
在许多情况下，尽管存在广泛炎症，肾移植仍可存活，使得排斥反应得以逆转。肾脏抵抗宿主效应机制的具体机制尚不清楚。在小鼠肾移植中，这种抵抗需要干扰素-γ（IFN-γ），它作用于移植物，在排斥反应的最初几天保护移植物免于坏死，并诱导主要组织相容性复合体（MHC）表达。由于IFN-γ的某些作用是由转录因子IRF-1介导的，因此研究了IRF-1在小鼠肾同种异体移植排斥反应供体组织早期阶段中的作用。将具有野生型IRF-1基因（WT）的小鼠或IRF-1基因被破坏的小鼠（IRF-1KO）的H-2(b)肾脏移植到CBA（H-2(k)）受体中。在第5天和第7天，尽管存在典型的排斥病理表现（间质浸润和肾小管炎），IRF-1KO和WT肾脏仍在发挥功能。然而，在排斥的IRF-1KO同种异体移植物中，功能迅速恶化，到第7天时伴有广泛的上皮坏死、肾小管周围毛细血管充血、肾小球炎和小静脉内纤维蛋白血栓形成。在第21天，尽管存在严重的肾小管炎和动脉炎，WT肾脏仍然存活，而IRF-1KO肾脏尽管大血管通畅，但上皮出现大量坏死。与WT肾脏相比，排斥的IRF-1KO肾脏显示出较低的供体MHC诱导，但穿孔素、颗粒酶B和Fas配体的mRNA水平相似，并引发宿主同种异体抗体反应。因此，在排斥的肾移植中，移植物中的IRF-1介导MHC诱导，但它也介导对坏死的抵抗，这一作用对于干预排斥反应的成功可能至关重要。
