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目的确定以肝脏为靶器官的基因治疗时急性肝炎的机制。方法用HE法和免疫组织化学法对8只恒河猴通过不同径路接受以腺病毒或Lipofectamine为载体的基因治疗时的免疫反应进行了研究。结果经静脉或胆管注入除去E_1,携带lacZ基因的腺病毒后1至3周发生了轻到中度急性肝炎。有病变的肝脏内 CD_3~+,CD_4~+和CD_8~+T细胞明显增多而B细胞缺如。肝细胞表面β_2-MG和HLA—DR也增多。免疫抑制治疗使急性肝炎和伴随的免疫反应延迟。结论腺病毒介导的基因治疗时肝脏的免疫反应是T细胞介导的,主要受Ⅰ型MHC限制。腺病毒载体和转基因均与肝损害有关。肝脏损害呈轻、中度,是可逆的。免疫抑制药物可延迟免疫性肝损害的发生并延长基因表达的时间。
Objective To determine the mechanism of acute hepatitis in gene therapy with liver as target organ. Methods HE and immunohistochemistry were used to study the immune response of 8 rhesus macaques treated with adenovirus or Lipofectamine as carriers. RESULTS: E_1 and lacc gene adenovirus were removed by intravenous or biliary injection, and mild to moderate acute hepatitis occurred 1 to 3 weeks after lacZ gene adenovirus infection. Lesions in the liver of CD_3 ~ +, CD_4 ~ + and CD_8 ~ + T cells were significantly increased and B cells absent. Liver cell surface β_2-MG and HLA-DR also increased. Immunosuppressive therapy delays acute hepatitis and the accompanying immune response. Conclusions Adenovirus-mediated gene therapy of liver immune response is T cell-mediated, mainly limited by type I MHC. Both adenoviral vectors and transgenes are associated with liver damage. Liver damage was mild, moderate, and reversible. Immunosuppressive drugs delay the onset of autoimmune liver damage and prolong the time of gene expression.