DataSheet_1_Response of Human Liver Tissue to Innate Immune Stimuli.pdf

Precision-cut human liver slice cultures (PCLS) have become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) using normal and diseased liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity in response to TLR3 and TLR4 agonists was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity: sustained abnormal immune gene expression in DAA-cured samples was identified in direct ex vivo measurements and in TLR3 and TLR4 stimulation assays. Genes that were up-regulated in chronic HCV-infected liver tissue were mostly characteristic of the non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying both liver pathology and innate immunity.

精准切割人肝切片培养（Precision-cut human liver slice cultures，PCLS）已成为临床前检测领域重要的替代免疫学研究平台。为进一步评估PCLS的应用潜能，本研究借助正常及病变肝组织，探究了其针对TLR3激动剂（poly-I:C）与TLR4激动剂（LPS，脂多糖）的先天免疫应答。病变肝组织来源于活动性慢性丙型肝炎病毒（Hepatitis C Virus，HCV）感染患者，以及经近期直接抗病毒药物（Direct-Acting Antiviral，DAA）治疗痊愈的既往慢性HCV感染患者。研究发现，与健康对照组相比，HCV感染组织中针对TLR3与TLR4激动剂的肝脏先天免疫应答非但未被抑制，反而得到增强。此外，尽管HCV已被近期清除，但经DAA治愈的肝组织仍存在持续的肝脏免疫异常：在直接离体检测与TLR3、TLR4刺激实验中，均观测到经DAA治愈的样本存在持续异常的免疫基因表达。慢性HCV感染肝组织中上调的基因大多具有非实质细胞区室的特征。上述结果证实了PCLS在肝脏病理学与先天免疫学研究中的应用价值。