Gene Expression Profiles Normalized in Psoriatic Skin by Treatment with Brodalumab, a Human Anti-IL-17 Receptor Monoclonal Antibody
Gene Expression Profiles Normalized in Psoriatic Skin by Treatment with Brodalumab, a Human Anti-IL-17 Receptor Monoclonal Antibody
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DOI：
10.4049/jimmunol.1301737
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发表时间：
2014-04-15
影响因子：
4.4
通讯作者：
Martin, David A.
中科院分区：
文献类型：
--
作者：
Russell, Chris B.;Rand, Hugh;Martin, David A.
IL-17通路是银屑病发病机制的一个确定的驱动因素。我们研究了IL-17受体a亚基竞争性抑制剂brodalumab治疗前后人银屑病皮肤中IL-17信号通路阻断的详细分子和细胞效应。在布罗达鲁单抗治疗后2周内，病变皮肤中数千个异常表达的基因正常化，病变牛皮癣转录组转化为与非病变皮肤相似。角化细胞表达的基因似乎很快正常化，而T细胞特异性的正常化发生在六周内。在病变皮肤中上调的三个IL-17配体基因，IL17A， IL17C和IL17F，在布罗达鲁单抗治疗后均以剂量依赖的方式下调。细胞测量也显示了类似的模式，角质细胞增生在一周内急剧减少，浸润性白细胞的减少发生在更长的时间尺度上。布罗达鲁单抗暴露量最高的个体显示il -17应答基因和银屑病转录组的正常化，而暴露量较低的受试者显示短暂或不完全的分子应答。临床和分子反应似乎依赖于相对于IL-17配体基因表达的布罗达鲁单抗暴露程度，IL-17信号传导减少到非病变范围与银屑病转录组正常化密切相关。这些数据表明，银屑病皮肤中IL-17信号的阻断最初会导致角化细胞表达基因的快速转录组变化，随后会导致白细胞异常的正常化，并证明IL-17R在角化细胞驱动疾病发病机制中的重要作用。
The IL-17 pathway is an established driver of psoriasis pathogenesis. We examined the detailed molecular and cellular effects of blockade of IL-17 signaling in human psoriatic skin before and following treatment with brodalumab, a competitive inhibitor of the IL-17 Receptor A subunit. Thousands of aberrantly expressed genes in lesional skin normalized within 2 weeks following brodalumab treatment, with conversion of the lesional psoriasis transcriptome to resemble that seen in nonlesional skin. Keratinocyteexpressed genes appeared to normalize rapidly, whereas T cell-specific normalization occurred over six weeks. The three IL-17 ligand genes that are upregulated in lesional skin, IL17A, IL17C, and IL17F, were all downregulated in a dose-dependent manner following brodalumab treatment. Cellular measures also showed a similar pattern with dramatic decreases in keratinocyte hyperplasia within one week, and decreases in infiltrating leukocytes occurred over a longer timescale. Individuals with the highest brodalumab exposure showed normalization of both IL-17-responsive genes and the psoriasis transcriptome, whereas subjects with lower exposures showed transient or incomplete molecular responses. Clinical and molecular response appeared dependent on the extent of brodalumab exposure relative to the expression of IL-17 ligand genes, and reduction of IL-17 signaling into the nonlesional range was strongly correlated with normalization of the psoriasis transcriptome. These data indicate that blockade of IL-17 signaling in psoriatic skin leads to rapid transcriptomal changes initially in keratinocyte-expressed genes, followed by normalization in the leukocyte abnormalities, and demonstrates the essential role of the IL-17R on keratinocytes in driving disease pathogenesis.