Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase
Tryptophan catabolism is associated with acute GVHD after human allogeneic stem cell transplantation and indicates activation of indoleamine 2,3-dioxygenase
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DOI：
10.1182/blood-2011-06-357814
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发表时间：
2011-12-22
期刊：
影响因子：
20.3
通讯作者：
Holler, Ernst
中科院分区：
文献类型：
--
作者：
Landfried, Karin;Zhu, Wentao;Holler, Ernst
吲哚胺2，3-双加氧酶（IDO）（色氨酸降解沿着犬尿氨酸途径中的限速酶）的诱导可作为有效的免疫调节环。为了解决其在人类异基因干细胞移植中的作用，我们测量了主要色氨酸代谢产物，如喹啉酸和犬尿氨酸，从51例患者的连续尿液标本，通过液相色谱-串联质谱。从入院到移植后90天收集样本，代谢物水平与早期临床事件和结果相关。在选定的患者中，通过定量RT-PCR在肠活检中评估IDO基因表达。与死于GVHD和相关并发症的患者（n = 10）相比，存活患者在第28、42和90天的代谢物水平分别显著降低。犬尿氨酸水平与GVHD的严重程度和临床病程直接相关：在没有急性GVHD的情况下，平均尿喹啉酸水平为4.5 +/- 0.3 μ mol/mmol肌酐，对于GVHD 1级或2级为8.0 +/- 1.1 μ mol/mmol肌酐，对于GVHD 3级或4级为13.5 +/- 2.7 μ mol/mmol肌酐（P < .001）。IDO的GVHD依赖性诱导通过来自患有严重GVHD的患者的肠活检组织中IDO mRNA的表达增加进一步表明。我们的数据表明在GVHD相关炎症中犬尿氨酸的反应性释放。（血。2011;118（26）：6971-6974）
Induction of indoleamine 2,3-dioxygenase (IDO), the rate-limiting enzyme in tryptophan degradation along the kynurenine pathway, acts as a potent immunoregulatory loop. To address its role in human allogeneic stem cell transplantation, we measured major tryptophan metabolites, such as quinolinic acid and kynurenine, in serial urine specimens from 51 patients by liquid chromatography-tandem mass spectrometry. Samples were collected between admission and day 90 after transplantation, and metabolite levels were correlated with early clinical events and outcome. In selected patients, IDO gene expression was assessed by quantitative RT-PCR in intestinal biopsies. Surviving patients had significantly lower metabolite levels on days 28, 42, and 90, respectively, compared with patients dying of GVHD and associated complications (n = 10). Kynurenine levels were directly correlated with severity and clinical course of GVHD: Mean urinary quinolinic acid levels were 4.5 +/- 0.3 mu mol/mmol creatinine in the absence of acute GVHD, 8.0 +/- 1.1 mu mol/mmol creatinine for GVHD grade 1 or 2, and 13.5 +/- 2.7 mu mol/mmol creatinine for GVHD grade 3 or 4 (P < .001), respectively. GVHD-dependent induction of IDO was further suggested by increased expression of IDO mRNA in intestinal biopsies from patients with severe GVHD. Our data indicate reactive release of kynurenines in GVHD-associated inflammation. (Blood. 2011;118(26):6971-6974)