Background

A standardized human model to study early pathogenic events in patients with psoriasis is missing. Activation of Toll-like receptor 7/8 by means of topical application of imiquimod is the most commonly used mouse model of psoriasis.

Objective

We sought to investigate the potential of a human imiquimod patch test model to resemble human psoriasis.

Methods

Imiquimod (Aldara 5% cream; 3M Pharmaceuticals, St Paul, Minn) was applied twice a week to the backs of volunteers (n = 18), and development of skin lesions was monitored over a period of 4 weeks. Consecutive biopsy specimens were taken for whole-genome expression analysis, histology, and T-cell isolation. Plasmacytoid dendritic cells (pDCs) were isolated from whole blood, stimulated with Toll-like receptor 7 agonist, and analyzed by means of extracellular flux analysis and real-time PCR.

Results

We demonstrate that imiquimod induces a monomorphic and self-limited inflammatory response in healthy subjects, as well as patients with psoriasis or eczema. The clinical and histologic phenotype, as well as the transcriptome, of imiquimod-induced inflammation in human skin resembles acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics the hallmarks of psoriasis. In contrast to classical contact dermatitis, in which myeloid dendritic cells sense haptens, pDCs are primary sensors of imiquimod. They respond with production of proinflammatory and T_H17-skewing cytokines, resulting in a T_H17 immune response with IL-23 as a key driver. In a proof-of-concept setting systemic treatment with ustekinumab diminished imiquimod-induced inflammation.

Conclusion

In human subjects imiquimod induces contact dermatitis with the distinctive feature that pDCs are the primary sensors, leading to an IL-23/T_H17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in patients with psoriasis.

中文翻译：

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Toll样受体7/8激动剂刺激浆细胞样树突状细胞在人类受试者中引发T _H 17减轻的急性接触性皮炎

背景

缺少研究牛皮癣患者早期致病事件的标准化人体模型。通过局部应用咪喹莫特激活Toll样受体7/8是牛皮癣最常用的小鼠模型。

客观的

我们试图研究人类咪喹莫特贴片测试模型类似人类牛皮癣的潜力。

方法

每周两次向志愿者（n = 18）的背部施用咪喹莫特（Aldara 5％乳膏； 3M Pharmaceuticals，明尼苏达州圣保罗），并在4周内监测皮肤病变的发展。连续活检标本用于全基因组表达分析，组织学和T细胞分离。从全血中分离浆细胞样树突状细胞（pDC），用Toll样受体7激动剂刺激，并通过细胞外通量分析和实时PCR进行分析。

结果

我们证明，咪喹莫特在健康受试者以及牛皮癣或湿疹患者中诱发单态性和自限性炎症反应。咪喹莫特诱发的人皮肤炎症的临床和组织学表型以及转录组，类似于急性接触性皮炎而不是牛皮癣。尽管如此，咪喹莫特模型模仿了牛皮癣的特征。与经典的接触性皮炎不同，在经典的接触性皮炎中，髓样树突状细胞可感觉到半抗原，而pDC是咪喹莫特的主要传感器。它们以促炎性和T _H 17倾斜的细胞因子的产生来响应，从而导致以IL-23为主要驱动力的T _H 17免疫应答。在概念验证的背景下，用优斯库单抗进行全身治疗可减少咪喹莫特引起的炎症。

结论

在人受试者中的咪喹莫特诱导接触与所述独特特征的pDC是主要传感器皮炎，导致IL-23 / T _ħ 17偏差。尽管存在这些缺点，但人类咪喹莫特模型可能有助于研究早期致病事件并证明牛皮癣患者的分子观念。