IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma
IL-21 induces in vivo immune activation of NK cells and CD8+ T cells in patients with metastatic melanoma and renal cell carcinoma
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DOI：
10.1007/s00262-008-0479-4
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发表时间：
2008-10-01
影响因子：
5.8
通讯作者：
Skak, Kresten
中科院分区：
文献类型：
--
作者：
Frederiksen, Klaus Stensgaard;Lundsgaard, Dorthe;Skak, Kresten
人白细胞介素-21 （IL-21）是一类细胞因子，先前在免疫应答性癌症的临床研究中报道过。在这里，我们报告了系统性IL-21治疗对免疫系统的影响，在两个1期试验中，这种新型细胞因子。重组IL-21以1 ~ 100 μ g/kg的剂量水平静脉丸注，采用两种计划治疗方案：每周3次，连续6周（3次/周）；或者每天一次，连续5天，然后9天无剂量（5 + 9）。在治疗期间，在外周血单核细胞（PBMC）中研究了以下生物标志物：STAT3的磷酸化，白细胞亚群组成的改变，体外细胞毒性，富集CD8+T细胞和CD56+NK细胞中效应分子的表达，以及CD8+T细胞的基因阵列分析。在所有剂量水平下均观察到IL-21的作用。在5 + 9方案中，IL-21诱导循环NK细胞和T细胞的剂量依赖性减少，然后在静息期恢复到基线水平。在CD8+ T细胞和CD56+NK细胞中，我们发现穿孔素和颗粒酶B mRNA上调。此外，CD8+T细胞的全转录组分析显示，与细胞周期进程、细胞运动性和免疫激活增加相关的几种转录物发生变化。最后，细胞毒性实验表明，IL-21增强了NK细胞体外杀死敏感靶点的能力。IL-21在所有剂量水平下都具有生物活性，并具有体内NK细胞和CD8+细胞活化的证据。
Human interleukin-21 (IL-21) is a class I cytokine previously reported in clinical studies on immune responsive cancers. Here we report the effects of systemic IL-21 therapy on the immune system in two phase 1 trials with this novel cytokine.Recombinant IL-21 was administered by intravenous bolus injection at dose levels from 1 to 100 mu g/kg using two planned treatment regimens: thrice weekly for 6 weeks (3/week); or once daily for five consecutive days followed by nine dose-free days (5 + 9). The following biomarkers were studied in peripheral blood mononuclear cells (PBMC) during treatment: phosphorylation of STAT3, alterations in the composition of leukocyte subsets, ex vivo cytotoxicity, expression of effector molecules in enriched CD8+T cells and CD56+NK cells by quantitative RT-PCR, and gene array profiling of CD8+T cells.Effects of IL-21 were observed at all dose levels. In the 5 + 9 regimen IL-21 induced a dose dependent decrease in circulating NK cells and T cells followed by a return to baseline in resting periods. In both CD8+ T cells and CD56+NK cells we found up-regulation of perforin and granzyme B mRNA. In addition, full transcriptome analysis of CD8+T cells displayed changes in several transcripts associated with increased cell cycle progression, cellular motility, and immune activation. Finally, cytotoxicity assays showed that IL-21 enhanced the ability of NK cells to kill sensitive targets ex vivo.IL-21 was biologically active at all dose levels administered with evidence of in vivo NK cell and CD8+ell activation.