Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation
Non-invasive monitoring of kidney allograft rejection through IDO metabolism evaluation
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DOI：
10.1038/sj.ki.5002023
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发表时间：
2007-01-01
影响因子：
19.6
通讯作者：
Fuchs, D.
中科院分区：
文献类型：
--
作者：
Brandacher, G.;Cakar, F.;Fuchs, D.
免疫调节酶吲哚胺2，3-双加氧酶（IDO）被干扰素-γ（IFN-γ）激活并通过色氨酸消耗，抑制炎症、宿主免疫防御和母体耐受中的适应性T细胞介导的免疫。其在实体器官移植中的作用仍不清楚。因此，我们研究了IDO介导的色氨酸催化剂在评估肾移植排斥反应中的有用性。从34例无排斥反应的肾移植患者和9例经活检证实的急性排斥反应患者（n = 12）中采集血液、尿液和组织样本。通过高压液相色谱法分析血清和尿液中犬尿氨酸和色氨酸的浓度。计算犬尿氨酸与色氨酸的比率（kyn/trp）以估计IDO活性。对肾活检进行IDO免疫染色。采用放射免疫法测定新蝶呤。Kyn/trp和新喋呤在健康志愿者血清中检测到低水平，在非排斥移植受者中升高。早在术后第1天，排斥反应受者的血清kyn/trp水平就高于非排斥反应受者。移植后13 ± 5.9天内发生的排斥反应伴随着血清（114 ± 44.5 μ mol/mmol，P = 0.001）和尿液（126 ± 65.9 μ mol/mmol，P = 0.02）中kyn/trp的升高，与移植物功能稳定期间的水平相比。Kyn/trp与新蝶呤显著相关，表明IFN-γ诱导的IDO活性增加。免疫组化显示IDO在排斥活检中上调，定位于肾小管上皮细胞。非排斥移植物显示无IDO表达。肾移植术后急性排斥反应与血、尿kyn/trp同时升高有关。因此，IDO活性可能提供一种新的非侵入性的手段，免疫监测肾移植物。
The immunomodulatory enzyme indoleamine 2,3-dioxygenase (IDO) is activated by interferon-gamma (IFN-gamma) and via tryptophan depletion, suppresses adaptive T cell-mediated immunity in inflammation, host immune defense, and maternal tolerance. Its role in solid organ transplantation is still unclear. Therefore, we investigated the usefulness of IDO-mediated tryptophan catabolism in the evaluation of kidney allograft rejection. Blood, urine, and tissue samples were collected from 34 renal transplant patients without rejection and from nine patients with biopsy-confirmed episodes of acute rejection (n = 12). Concentrations of kynurenine and tryptophan in serum and urine were analyzed by high-pressure liquid chromatography. Kynurenine to tryptophan ratio (kyn/trp) was calculated to estimate IDO activity. Immunostaining for IDO was performed on renal biopsies. Neopterin was assessed using radioimmunoassay. Kyn/trp and neopterin were detectable at low levels in serum of healthy volunteers and were increased in non-rejecting allograft recipients. Serum levels of kyn/trp were higher in recipients with rejection compared to non-rejectors as early as by day 1 post-surgery. Rejection episodes occurring within 13 +/- 5.9 days after transplantation were accompanied by elevated kyn/trp in serum (114 +/- 44.5 mu mol/mmol, P = 0.001) and urine (126 +/- 65.9 mu mol/mmol, P = 0.02) compared to levels during stable graft function. Kyn/trp correlated significantly with neopterin suggesting an IFN-gamma-induced increase in IDO activity. Immunostaining showed upregulation of IDO in rejection biopsies, localized in tubular-epithelial cells. Non-rejected grafts displayed no IDO expression. Acute rejection is associated with simultaneously increased serum and urinary kyn/trp in patients after kidney transplantation. Thus, IDO activity might offer a novel non-invasive means of immunomonitoring of renal allografts.