Attenuation of NK Cell-mediated Liver Injury Through Genetically Manipulating IL-10, CCL5 and CX3CL1 by a Liver-directed Multifunction Vector
作者单位：Department of Immunology School of Life Sciences University of Science and Technology of China Hefei National Laboratory for Physical Sciences at Microscale
会议名称：《第八届全国免疫学学术大会》
会议日期：2012年
学科分类：1002[医学-临床医学] 100201[医学-内科学(含：心血管病、血液病、呼吸系病、消化系病、内分泌与代谢病、肾病、风湿病、传染病)] 10[医学]
关 键 词：hepatocyte-specific RNA interference adenoviral vector multiple target liver inflammation
摘 要：Background/Aims:Adenovirus or adenovirus-based vectors were reported to induce serious liver inflammation in a natural killer(NK) cell-dependent manner, which limits its clinical applicability for liver gene *** tried to develop an efficient liver-specific therapeutic approach to control hepatic NK cell function via simultaneously manipulating multiple immune ***:After comparing various promoters, we selected a highly efficient hepatocyte-specific AFP enhancer/albumin ***-specific RNA interference was realized by microRNA-based shRNA transcribed from the hepatocyte-specific RNA polymerase II ***-specific multiple function vectors were constructed and applied in vitro and in ***:A multi-reporter vector simultaneously over-expressing both β-galactosidase(Lac Z) and Ds Red2 and knocking down both EGFP and luciferase was constructed and functionally *** used this hepatocyte-specific multiple function vector template to over-express both Ds Red2 and human IL-10(hu IL10) and interfere with CCL5 and CX3CL1(FKN) expression using 3 target sequences per chemokine;in total, these 8 functional fragments synergized to attenuate adenovirus-induced acute hepatitis by reducing liver NK cell number/activation and serum IFN-γ and TNF-α.The multiple function vectors could be delivered by non-viral(hydrodynamic injection) and viral(adenovirus) approaches, and maintained long-term function(more than 3 months in mice).Conclusions:Our results suggest a possible extensive and practical utilization for this novel multifunctional *** liver diseases, such as malignancies and hepatitis, correlate with immune gene disorders, our study provides new insight into exploring the therapeutic applicability of a single vector that can manipulate multiple genes in a liver-specific manner.