Major differences between human atopic dermatitis and murine models, as determined by using global transcriptomic profiling

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY

卷:139

Article

Ewald, David A.^1,2,3  Noda, Shinji¹  Oliva, Margeaux^4,5  Litman, Thomas^2,8  Nakajima, Saeko⁹  Li, Xuan¹  Xu, Hui⁴  Workman, Christopher T.³  Scheipers, Peter²  Svitacheva, Naila¹⁰  Labuda, Tord¹¹  Krueger, James G.¹  Suarez-Farinas, Mayte^1,6,7  Kabashima, Kenji^9,12,13  Guttman-Yassky, Emma^1,4,5 

[1] Rockefeller Univ, Invest Dermatol Lab, 1230 York Ave, New York, NY 10021 USA

[2] LEO Pharma AS, Exploratory Biol, Ballerup, Denmark

[3] Tech Univ Denmark, Ctr Biol Sequence Anal, Dept Syst Biol, Regulatory Genom,Integrat Syst Biol, Lyngby, Denmark

[4] Icahn Sch Med Mt Sinai, Dept Dermatol, New York, NY 10029 USA

[5] Icahn Sch Med Mt Sinai, Lab Inflammatory Skin Dis, New York, NY 10029 USA

[6] Icahn Sch Med Mt Sinai, Dept Dermatol, Dept Populat Hlth Sci & Policy, New York, NY 10029 USA

[7] Icahn Sch Med Mt Sinai, Icahn Inst Genom & Multiscale Biol, New York, NY 10029 USA

[8] Univ Copenhagen, Fac Hlth & Med Sci, Dept Immunol & Microbiol, Copenhagen, Denmark

[9] Kyoto Univ, Grad Sch Med, Dept Dermatol, Kyoto, Japan

[10] LEO Pharma AS, Vivo Biol, Ballerup, Denmark

[11] LEO Pharma AS, Translat Med, Ballerup, Denmark

[12] ASTAR, Singapore Immunol Network SIgN, Singapore, Singapore

[13] ASTAR, Inst Med Biol, Singapore, Singapore

关键词: Atopic dermatitis;    TH1;    TH2;    TH17;    psoriasis;    contact dermatitis;    mouse model;    NC/Nga;    filaggrin;    oxazolone;    ovalbumin;    IL-2;   

DOI  :  10.1016/j.jaci.2016.08.029

来源: Elsevier

【 摘 要 】

Background: Atopic dermatitis (AD) is caused by a complex interplay between immune and barrier abnormalities. Murine models of AD are essential for preclinical assessments of new treatments. Although many models have been used to simulate AD, their transcriptomic profiles are not fully understood, and a comparison of these models with the human AD transcriptomic fingerprint is lacking. Objective: We sought to evaluate the transcriptomic profiles of 6 common murine models and determine how they relate to human AD skin. Methods: Transcriptomic profiling was performed by using microarrays and quantitative RT-PCR on biopsy specimens from NC/Nga, flaky tail, Flg-mutated, ovalbumin-challenged, oxazolone-challenged, and IL-23-injected mice. Gene expression data of patients with AD, psoriasis, and contact dermatitis were obtained from previous patient cohorts. Criteria of a fold change of 2 or greater and a false discovery rate of 0.05 or less were used for gene arrays. Results: IL-23-injected, NC/Nga, and oxazolone-challenged mice show the largest homology with our human meta-analysisderived AD transcriptome (37%, 18%, 17%, respectively). Similar to human AD, robust T(H)1, T(H)2, and also T(H)17 activation are seen in IL-23-injected and NC/Nga mice, with similar but weaker inflammation in ovalbumin-challenged mice. Oxazolone-challenged mice show a TH1-centered reaction, and flaky tail mice demonstrate a strong TH17 polarization. Flg-mutated mice display filaggrin downregulation without significant inflammation. Conclusion: No single murine model fully captures all aspects of the AD profile; instead, each model reflects different immune or barrier disease aspects. Overall, among the 6 murine models, IL-23-injected mice best simulate human AD; still, the translational focus of the investigation should determine which model is most applicable.

【 授权许可】

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