Upregulation of class I major histocompatibility complex antigens by interferon gamma is necessary for T-cell-mediated elimination of recombinant adenovirus-infected hepatocytes in vivo.

Recombinant adenoviruses are attractive vehicles for liver-directed gene therapy because of the high efficiency with which they transfer genes to hepatocytes in vivo. First generation recombinant adenoviruses deleted of E1 sequences also express recombinant and early and late viral genes, which lead to development of destructive cellular immune responses. Previous studies indicated that class I major histocompatibility complex (MHC)-restricted cytotoxic T lymphocytes (CTLs) play a major role in eliminating virus-infected cells. The present studies utilize mouse models to evaluate the role of T-helper cells in the primary response to adenovirus-mediated gene transfer to the liver. In vivo ablation of CD4+ cells or interferon gamma (IFN-gamma) was sufficient to prevent the elimination of adenovirus-transduced hepatocytes, despite the induction of a measurable CTL response. Mobilization of an effective TH1 response as measured by in vitro proliferation assays was associated with substantial upregulation of MHC class I expression, an effect that was prevented in IFN-gamma-deficient animals. These results suggest that elimination of virus-infected hepatocytes in a primary exposure to recombinant adenovirus requires both induction of antigen-specific CTLs as well as sensitization of the target cell by TH1-mediated activation of MHC class I expression.

重组腺病毒是肝脏导向基因治疗的理想载体，因为它们在体内将基因转移到肝细胞的效率很高。缺失E1序列的第一代重组腺病毒也会表达重组的以及早期和晚期病毒基因，这会导致破坏性的细胞免疫反应的产生。先前的研究表明，I类主要组织相容性复合体（MHC）限制的细胞毒性T淋巴细胞（CTLs）在清除病毒感染细胞中起主要作用。本研究利用小鼠模型来评估辅助性T细胞在腺病毒介导的肝脏基因转移的初次应答中的作用。体内清除CD4⁺细胞或干扰素γ（IFN - γ）足以阻止腺病毒转导的肝细胞被清除，尽管诱导了可检测的CTL反应。通过体外增殖试验检测到的有效TH1反应的调动与MHC I类表达的大幅上调有关，而在IFN - γ缺陷动物中这种作用被阻止。这些结果表明，在初次接触重组腺病毒时清除病毒感染的肝细胞既需要诱导抗原特异性CTLs，也需要通过TH1介导的MHC I类表达激活使靶细胞致敏。