Department of Biomedical Engineering, National University of Singapore, Singapore.
Lab Chip. 2018 Oct 23;18(21):3239-3250. doi: 10.1039/c8lc00790j.
Drug-induced skin sensitization is prevalent worldwide and can trigger life-threatening health conditions, such as Stevens Johnson Syndrome. However, existing in vitro skin models cannot adequately predict the skin sensitization effects of drugs administered into the systemic circulation because dermal inflammation and injury are preceded by conversion of parent drugs into antigenic reactive metabolites in the liver and subsequent activation of the immune system. Here, we demonstrate that recapitulation of these early tandem cellular processes in a compartmentalized liver-immune coculture array is sufficient to predict the skin sensitization potential of systemic drugs. Human progenitor cell (HepaRG)-derived hepatocyte spheroids and U937 myeloid cells, a representative antigen presenting cell (APC), can maintain their respective functions in 2 concentric micro-chambers, which are connected by a diffusion microchannel network. Paradigm drugs that are reported to cause severe cutaneous drug reactions (i.e. carbamazepine, phenytoin and allopurinol) can be metabolized into their reactive metabolites, which diffuse efficiently into the adjoining immune compartment within a 48 hour period. By measuring the extent of U937 activation as indicated by IL8, IL1β and CD86 upregulation upon drug administration, we show that the liver-immune coculture array more consistently and reliably distinguish all 3-paradigm skin sensitizing drugs from a non-skin sensitizer than conventional bulk Transwell coculture. Given its miniaturized format, design simplicity and prediction capability, this novel in vitro system can be readily scaled into a screenable platform to identify the skin sensitization potential of systemically-administered drugs.
药物诱导的皮肤致敏在全球范围内很普遍，可引发危及生命的健康问题，例如史蒂文斯-约翰逊综合征。然而，现有的体外皮肤模型无法充分预测全身性给药药物的皮肤致敏效应，因为皮肤炎症和损伤发生之前，亲代药物在肝脏中转化为抗原反应性代谢物，随后激活免疫系统。在这里，我们证明，在分隔的肝-免疫共培养阵列中再现这些早期串联的细胞过程足以预测全身性药物的皮肤致敏潜力。人源祖细胞（HepaRG）衍生的肝细胞球体和 U937 髓样细胞（一种代表性的抗原呈递细胞 (APC)）可在 2 个同心微室中维持各自的功能，这 2 个微室通过扩散微通道网络连接。据报道，一些会引起严重皮肤药物反应的范例药物（即卡马西平、苯妥英和别嘌醇）可被代谢成其反应性代谢物，这些代谢物在 48 小时内可有效地扩散到相邻的免疫隔室中。通过测量药物给药后 U937 激活的程度（如通过 IL8、IL1β 和 CD86 的上调来指示），我们表明肝-免疫共培养阵列比传统的 Transwell 共培养更一致且可靠地区分这 3 种范例皮肤致敏药物和非皮肤致敏药物。鉴于其微型化格式、设计简单性和预测能力，这种新型体外系统可容易扩展为可筛选的平台，以识别全身性给药药物的皮肤致敏潜力。
