Mouse models of atopic dermatitis: a critical reappraisal
Mouse models of atopic dermatitis: a critical reappraisal
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DOI：
10.1111/exd.14270
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发表时间：
2021-01-09
影响因子：
3.6
通讯作者：
Paus, Ralf
中科院分区：
文献类型：
--
作者：
Gilhar, Amos;Reich, Kristian;Paus, Ralf
特应性皮炎（AD）的小鼠模型是一种不可或缺的临床前研究工具，用于测试新的候选AD治疗剂和询问体内AD病理生物学。在这个观点中，我们描述了为什么，不幸的是，没有一个目前可用的所谓的“AD”小鼠模型令人满意地反映了人类AD的临床复杂性，但模拟更多的“过敏性”或“冲洗性”接触性皮炎条件。该评价限制了AD模型对新测试的候选AD治疗剂的临床结果的预测价值和小鼠模型对人类AD病理生理学研究的可靠性。在这里，我们建议发起一个理性的辩论的最低标准，小鼠模型应满足，以被认为是相关的人类AD。我们认为有效的AD模型至少应满足以下标准：（a）AD样表皮屏障缺陷，伴丝聚蛋白表达减少沿着过度增殖、增生;（B）胸腺基质淋巴细胞生成素（TSLP）、骨膜蛋白和/或趋化因子如TARC（CCL 17）的表皮表达增加;（c）特征性真皮免疫细胞浸润，具有一些关键细胞因子如IL-4、IL-13、IL-31和IL-33的过表达;（d）独特的“神经性皮炎”特征（感觉皮肤神经支配过度、β-肾上腺素能信号传导缺陷、神经源性皮肤炎症和由感知的压力引起的AD样皮肤病变的触发或加重）;和（e）实验诱导的皮肤病变对标准AD治疗的反应。最后，我们描述了为什么人源化AD小鼠模型（SCID小鼠上的人皮肤异种移植）提供了一个特别有前途的临床前研究替代目前可用的“AD”小鼠模型。
Mouse models for atopic dermatitis (AD) are an indispensable preclinical research tool for testing new candidate AD therapeutics and for interrogating AD pathobiology in vivo. In this Viewpoint, we delineate why, unfortunately, none of the currently available so-called "AD" mouse models satisfactorily reflect the clinical complexity of human AD, but imitate more "allergic" or "irriant" contact dermatitis conditions. This evaluation limits the predictive value of AD models for clinical outcomes of new tested candidate AD therapeutics and the instructiveness of mouse models for human AD pathophysiology research. Here, we propose initiating a rational debate on the minimal criteria that a mouse model should meet in order to be considered relevant for human AD. We suggest that valid AD models should at least meet the following criteria: (a) an AD-like epidermal barrier defect with reduced filaggrin expression along with hyperproliferation, hyperplasia; (b) increased epidermal expression of thymic stromal lymphopoietin (TSLP), periostin and/or chemokines such as TARC (CCL17); (c) a characteristic dermal immune cell infiltrate with overexpression of some key cytokines such as IL-4, IL-13, IL-31 and IL-33; (d) distinctive "neurodermatitis" features (sensory skin hyperinnervation, defective beta-adrenergic signalling, neurogenic skin inflammation and triggering or aggravation of AD-like skin lesions by perceived stress); and (e) response of experimentally induced skin lesions to standard AD therapy. Finally, we delineate why humanized AD mouse models (human skin xenotransplants on SCID mice) offer a particularly promising preclinical research alternative to the currently available "AD" mouse models.