Increased expression of erythropoiesis inhibiting cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy
Increased expression of erythropoiesis inhibiting cytokines (IFN-γ, TNF-α, IL-10, and IL-13) by T cells in patients exhibiting a poor response to erythropoietin therapy
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DOI：
10.1097/01.asn.0000071514.36428.61
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发表时间：
2003-07-01
影响因子：
13.6
通讯作者：
MacDougall, IC
中科院分区：
文献类型：
--
作者：
Cooper, AC;Mikhail, A;MacDougall, IC
对重组人促红细胞生成素的耐药发生在一小部分但很重要的血液透析患者中。这可能是由于增加的免疫激活，因为促炎细胞因子抑制体外红细胞生成。使用FACScan流式细胞术，PMA/离子霉素刺激的T细胞表达细胞因子的比例离体比较在18个不良反应者促红细胞生成素，14个良好反应者促红细胞生成素，和14个正常对照。与良好应答者（11 +/-6%，P < 0.001）和对照组（12 +/-6%，P <0.01）相比，来自不良应答者的CD 4 + T细胞表达更多的干扰素-γ（IFN-γ; 19 +/-6%）。类似地，来自不良反应者的CD 4 + T细胞表达更多的肿瘤坏死因子-α（TNF-α;不良反应者：51 +/-19%;良好反应者：27 +/-15%[P < 0.01]和对照组：30 +/-19%[P < 0.01]）。IL-10的CD 4（+）表达也增强（不良反应者：1.6 +/- 1.1%，良好反应者：0.7 +/- 0.6% [P < 0.05]，对照组：0.5 +/- 0.2% [P < 0.01]）。同样，白细胞介素13（IL-13）的CD 4（+）表达增加（不良反应者：4.4 +/- 4.2%，良好反应者：1.6 +/- 1.7% [P < 0.05]和对照组：1.6 +/- 1.5% [P < 0.05]）。来自低应答者的CD 8（+）T细胞也显示出细胞因子的表达增强。对于IFN-γ，低应答者表达为48 +/- 20%，而良好应答者为31 +/- 17%（P < 0.05），对照组为23 +/- 15%（P < 0.01）。不良反应者的TNF-α表达为41 +/- 21%，而良好反应者为25 +/- 14%（P < 0.05），对照组为21 +/- 15%（P <0.01）。低应答者的IL-10表达为2.0 +/- 1.2%（良好应答者：0.7 +/- 0.6% [P < 0.01];对照组：0.5 +/- 0.2% [P < 0.001]）。这些数据表明，来自不良反应者的T细胞处于增强的活化状态，这可能是慢性炎症的结果。在没有任何其他原因（如缺铁）的情况下，细胞因子的过度产生可能导致肾衰竭患者对红细胞生成治疗的低反应性。
Resistance to recombinant human erythropoietin occurs in a small but important proportion of hemodialysis patients. This may be due to increased immune activation because pro-inflammatory cytokines inhibit erythropoiesis in vitro. Using FACScan flow cytometry, the proportion of PMA/ionomycin-stimulated T cells expressing cytokines ex vivo was compared in 18 poor responders to erythropoictin, 14 good responders to erythropoietin, and 14 normal controls. CD4+ T cells from poor responders expressed more interferon-gamma (IFN-gamma; 19 +/- 6%) compared with good responders (11 +/- 6%, P < 0.001) and controls (12 +/- 6%, P < 0.01). Similarly, CD4+ T cells from poor responders expressed more tumor necrosis factor-alpha (TNF-alpha; poor responders: 51 +/- 19% versus good responders: 27 +/- 15% [P < 0.01] and controls: 30 +/- 19% [P < 0.01]). CD4(+) expression of IL-10 was also enhanced (poor responders: 1.6 +/- 1.1% versus good responders: 0.7 +/- 0.6% [P < 0.05] and controls: 0.5 +/- 0.2% [P < 0.01]). Likewise, CD4(+) expression of interleukin-13 (IL-13) was increased (poor responders: 4.4 +/- 4.2% versus good responders: 1.6 +/- 1.7% [P < 0.05] and controls: 1.6 +/- 1.5% [P < 0.05]). CD8(+) T cells from poor responders also showed enhanced expression of cytokines. For IFN-gamma, poor responder expression was 48 +/- 20% compared with 31 +/- 17% (P < 0.05) for good responders and 23 +/- 15% (P < 0.01) for controls. TNF-alpha expression for poor responders was 41 +/- 21% versus 25 +/- 14% for good responders (P < 0.05) and 21 +/- 15% for controls (P < 0.0 1). IL-10 expression for poor responders was 2.0 +/- 1.2% (good responders: 0.7 +/- 0.6% [P < 0.01]; controls: 0.5 +/- 0.2% [P < 0.001]). These data indicate that T cells from poor responders are in an enhanced activation state possibly as a result of chronic inflammation. In the absence of any other cause (such as iron deficiency), the overproduction of cytokines may account for hyporesponsiveness to erythropoietic therapy in patients with renal failure.