Alopecia areata: Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies.
Alopecia areata: Animal models illuminate autoimmune pathogenesis and novel immunotherapeutic strategies.
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DOI：
10.1016/j.autrev.2016.03.008
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发表时间：
2016-07
影响因子：
13.6
通讯作者：
Paus R
中科院分区：
文献类型：
--
作者：
Gilhar A;Schrum AG;Etzioni A;Waldmann H;Paus R
斑秃是人类最常见的自身免疫性疾病之一，其特征是突然的、经常持续的和心理上毁灭性的脱发。动物模型极大地帮助阐明AA中关键的细胞和分子免疫途径。两种最突出的是自发地或在实验诱导后形成AA样毛发表型的近交系C3 H/HeJ小鼠，以及异种移植到SCID小鼠上的健康人头皮皮肤，其中通过皮内注射富含CD 56 +/NKG 2D+细胞的IL-2刺激的PBMC诱导人AA的表型。目前的审查严格审查的优点和缺点的AA动物模型，以及它们如何塑造我们的理解AA病理生物学，和新的治疗策略的发展。AA被认为是在毛囊（HF）的天然免疫赦免（IP）崩溃时出现的，诱导HF上皮中的异位MHC I类表达和自身抗原呈递给自身反应性CD 8 + T细胞。与其他自身免疫性疾病一样，IFN-γ和IL-15的上调与AA发病机制密切相关，NKG 2D及其配体、云母和ULBP 3也是如此。C3 H/HeJ小鼠模型用于鉴定鼠AA中的关键免疫细胞和分子原理，以及Janus激酶（JAK）抑制剂是用于体内AA管理的合适药剂的原理证明，因为IFN-γ和IL-15均通过JAK途径发出信号。相反，AA的人源化小鼠模型已被用于证明先前假设的CD 8 + T细胞和NKG 2D+细胞在AA发病机制中的关键作用，并发现人类特异性药理学靶点，如钾通道Kv1.3，并显示PDE 4抑制剂阿普斯特抑制人类皮肤中的AA发展。因此，AA提供了一种模型疾病，其中考虑在人类自身免疫性疾病的临床前研究中选择适当的动物模型时所面临的一般挑战、机会和限制。
One of the most common human autoimmune diseases, alopecia areata (AA), is characterized by sudden, often persisting and psychologically devastating hair loss. Animal models have helped greatly to elucidate critical cellular and molecular immune pathways in AA. The two most prominent ones are inbred C3H/HeJ mice which develop an AA-like hair phenotype spontaneously or after experimental induction, and healthy human scalp skin xenotransplanted onto SCID mice, in which a phenocopy of human AA is induced by injecting IL-2-stimulated PBMCs enriched for CD56+/NKG2D+ cells intradermally. The current review critically examines the pros and cons of the available AA animal models and how they have shaped our understanding of AA pathobiology, and the development of new therapeutic strategies. AA is thought to arise when the hair follicle’s (HF) natural immune privilege (IP) collapses, inducing ectopic MHC class I expression in the HF epithelium and autoantigen presentation to autoreactive CD8+ T cells. In common with other autoimmune diseases, upregulation of IFN-γ and IL-15 is critically implicated in AA pathogenesis, as are NKG2D and its ligands, MICA, and ULBP3. The C3H/HeJ mouse model was used to identify key immune cell and molecular principles in murine AA, and proof-of-principle that Janus kinase (JAK) inhibitors are suitable agents for AA management in vivo, since both IFN-γ and IL-15 signal via the JAK pathway. Instead, the humanized mouse model of AA has been used to demonstrate the previously hypothesized key role of CD8+ T cells and NKG2D+ cells in AA pathogenesis and to discover human-specific pharmacologic targets like the potassium channel Kv1.3, and to show that the PDE4 inhibitor, apremilast, inhibits AA development in human skin. As such, AA provides a model disease, in which to contemplate general challenges, opportunities, and limitations one faces when selecting appropriate animal models in preclinical research for human autoimmune diseases.