Department of Molecular and Clinical Medicine (Nephrology), University of Gothenburg, Gothenburg, Sweden.
Transplantation. 2009 Oct 15;88(7):911-9. doi: 10.1097/TP.0b013e3181b72e49.
In the clinical setting, transplanted liver seems to protect other grafts from the same donor from rejection. Our previous findings suggest that an auxiliary liver transplantation a few hours before a renal transplantation not only inhibits hyperacute antibody-mediated rejection but also improves long-term kidney graft survival in sensitized recipients. Here, we investigated indoleamine 2,3-dioxygenase (IDO) activity, as one potential mechanism for liver-induced long-term acceptance of kidney grafts.
Tryptophan degradation was measured to estimate IDO activity in patient sera and cell culture supernatants with high performance liquid chromatography. Gene expression in the grafted organs and cell lysates was studied using real time polymerase chain reaction analysis.
Tryptophan degradation increased in peripheral blood from patients undergoing combined auxiliary liver-kidney transplantation, whereas it decreased in patients after regular renal transplantation. A 100-fold increase in IDO mRNA, preceded by upregulation of the IDO-inducing cytokines tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma, was observed in the transplanted organs after graft reperfusion in patients undergoing combined graft transplantation. Subsequent studies in vitro revealed that immature dendritic cells, but not hepatocytes, strongly activated IDO on maturation with tumor necrosis factor-alpha, interleukin-1beta, and interferon-gamma. Finally, serum from liver-transplanted patients elicited an even stronger IDO-activity in such cytokine-stimulated dendritic cells.
Taken together these findings suggest that the liver-induced long-term acceptance seen in human combined auxiliary liver and kidney transplantation is at least partly mediated by IDO activity.
在临床环境中，移植肝脏似乎可以保护同一供体的其他移植物免受排斥。我们之前的研究结果表明，在肾移植前数小时进行辅助性肝移植不仅可以抑制超急性抗体介导的排斥反应，而且还可以改善致敏受者的长期肾脏移植物存活率。在这里，我们研究了吲哚胺 2,3-双加氧酶（IDO）活性，作为肝脏诱导长期接受肾脏移植物的一种潜在机制。
采用高效液相色谱法测量色氨酸降解以估计患者血清和细胞培养上清液中的 IDO 活性。使用实时聚合酶链反应分析研究移植物器官和细胞裂解物中的基因表达。
接受联合辅助性肝-肾移植的患者外周血中色氨酸降解增加，而常规肾移植后的患者色氨酸降解减少。在联合移植患者中，在移植物再灌注后，在移植器官中观察到 IDO mRNA 增加了 100 倍，并且 IDO 诱导细胞因子肿瘤坏死因子-α，白细胞介素-1β和干扰素-γ的表达上调。随后的体外研究表明，不成熟的树突状细胞（而非肝细胞）在用肿瘤坏死因子-α，白细胞介素-1β和干扰素-γ成熟时强烈激活 IDO。最后，来自肝移植患者的血清在这种细胞因子刺激的树突状细胞中引发了更强的 IDO 活性。
综上所述，这些发现表明，在人类联合辅助性肝和肾移植中观察到的肝脏诱导的长期接受至少部分是由 IDO 活性介导的。
