DeMatteo R P, Markmann J F, Kozarsky K F, Barker C F, Raper S E
Institute for Human Gene Therapy, University of Pennsylvania Medical Center, Philadelphia, USA.
Gene Ther. 1996 Jan;3(1):4-12.
Although first generation recombinant adenoviruses are efficient vehicles for gene transfer, their immunogenicity precludes long-term persistence. We show that adenoviral transgene expression in the liver of normal mice is prolonged from a baseline of less than 2 weeks to 7 weeks by depleting CD4+ T lymphocytes with thymectomy and a 3-day course of anti-CD4 monoclonal antibody or by nonselectively depleting T cells with a single dose of anti-thymocyte serum (ATS). Transgene expression persisted despite the development of an antiviral humoral immune response by 3 weeks after virus administration. In vitro assays of T lymphocyte function revealed an initial diminished capacity to proliferate in the presence of adenoviral antigens in animals depleted of CD4+ T cells or given anti-thymocyte serum. Eventual loss of recombinant gene expression coincided with the development of adenovirus-specific cytotoxic T lymphocyte activity in vitro. Immunosuppression provides a useful experimental tool to elucidate the immunobiology of recombinant adenoviruses and may have clinical application to adenovirus-mediated gene therapy.
尽管第一代重组腺病毒是基因转移的有效载体，但其免疫原性妨碍了长期存留。我们发现，通过胸腺切除术和3天疗程的抗CD4单克隆抗体清除CD4+ T淋巴细胞，或通过单剂量抗胸腺细胞血清（ATS）非选择性地清除T细胞，正常小鼠肝脏中的腺病毒转基因表达可从不到2周的基线延长至7周。尽管在病毒给药后3周出现了抗病毒体液免疫反应，但转基因表达仍持续存在。对T淋巴细胞功能的体外分析显示，在清除CD4+ T细胞或给予抗胸腺细胞血清的动物中，最初在腺病毒抗原存在下增殖的能力有所下降。重组基因表达的最终丧失与体外腺病毒特异性细胞毒性T淋巴细胞活性的发展相一致。免疫抑制为阐明重组腺病毒的免疫生物学提供了一个有用的实验工具，并且可能在腺病毒介导的基因治疗中具有临床应用价值。
