McMaster University, Medicine , 1200 Main St West, Hamilton, Ontario, L8N 3Z5 , Canada
Expert Opin Ther Targets. 2014 Jul;18(7):771-85. doi: 10.1517/14728222.2014.915314.
Epithelial cell-derived mediators have emerged as key players for instigating local remodeling and the associated cellular inflammation in asthmatic airways. In particular, the epithelial-derived cytokine, thymic stromal lymphopoietin (TSLP), has been identified as a master switch for allergic inflammation.
TSLP is expressed by structural and immune cells at the site of allergen entry in the airways. Stimuli for release of TSLP include common triggers of asthma symptoms, and TSLP levels correlate with disease severity. TSLP regulates helper T cell 2 (Th2) humoral immunity through upregulating OX40L on dendritic cells (DCs), which drives Th2 lymphocytes; however, activation of several other cells by TSLP also supports the development of Th2 inflammation. Animal models of asthma demonstrate that increased levels of TSLP can induce many of the characteristics of asthma.
The work conducted to date supports a critical role of TSLP in the pathogenesis of allergic asthma. The first clinical trial to block the downstream effects of OX40L has shown reduced levels of circulating IgE and airway eosinophils, confirming the importance of TSLP-induced OX40L levels on DCs. Clinical trials with TSLP blockade are underway and will unequivocally confirm whether TSLP is indeed a key driver of allergic inflammation in asthma.
上皮细胞衍生的介质已成为引发哮喘气道局部重塑和相关细胞炎症的关键因素。特别是上皮细胞衍生的细胞因子胸腺基质淋巴细胞生成素 (TSLP)，已被确定为过敏炎症的主开关。
TSLP 由气道过敏原进入部位的结构细胞和免疫细胞表达。TSLP 释放的刺激物包括哮喘症状的常见诱因，并且 TSLP 水平与疾病严重程度相关。TSLP 通过上调树突状细胞 (DC) 上的 OX40L 来调节辅助性 T 细胞 2 (Th2) 体液免疫，从而驱动 Th2 淋巴细胞；然而，TSLP 对其他几种细胞的激活也支持 Th2 炎症的发展。哮喘的动物模型表明，TSLP 水平的增加可诱导哮喘的许多特征。
迄今为止开展的工作支持 TSLP 在过敏性哮喘发病机制中的关键作用。阻断 OX40L 下游效应的首个临床试验显示循环 IgE 和气道嗜酸性粒细胞水平降低，证实了 TSLP 诱导的 DC 上 OX40L 水平的重要性。TSLP 阻断的临床试验正在进行中，将明确证实 TSLP 是否确实是哮喘中过敏炎症的关键驱动因素。
