Stein C S, Pemberton J L, van Rooijen N, Davidson B L
Department of Internal Medicine, University of Iowa College of Medicine, Iowa City 52242, USA.
Gene Ther. 1998 Apr;5(4):431-9. doi: 10.1038/sj.gt.3300616.
The anti-CD40 ligand antibody MR-1, and macrophage-depleting liposomes were tested for their ability as transient immunosuppressive agents to: (1) prolong transgene expression; and (2) permit redosing after recombinant adenovirus infusion of mice. To test for effect on transgene duration, mice were infused with recombinant adenovirus coding for human factor IX (AdFIX), and plasma FIX levels monitored over time. Treatment with either agent significantly prolonged transgene expression. Persistence was accompanied by inhibition of anti-adenovirus (anti-Ad) IgG, and decreased IL-10 and IFN-gamma production from splenic lymphocytes re-exposed to virus particles in vitro. To test for effect on redosing, mice were given a primary infusion of recombinant adenovirus coding for bacterial beta-galactosidase (Ad beta gal), followed by secondary and tertiary infusions of AdFIX on days 24 and 63. Mice that had received MR-1 had low to undetectable anti-Ad on day 24, and efficient transduction occurred. Furthermore, FIX levels endured in these mice, with 40% retention of FIX on day 63, in contrast to rapid loss in naive controls. On day 63, the continuance of negligible anti-Ad levels correlated with successful tertiary transduction. These results suggest that both macrophage depletion and CD40 ligand blockade inhibit immune responses to recombinant adenovirus to slow decline of transgene expression, while only CD40 ligand blockade inhibits anti-Ad antibody generation sufficiently to allow redosing to the liver.
对抗CD40配体抗体MR-1和巨噬细胞清除脂质体作为瞬时免疫抑制剂的能力进行了测试，以：（1）延长转基因表达；（2）在向小鼠输注重组腺病毒后允许再次给药。为了测试对转基因持续时间的影响，给小鼠输注编码人因子IX的重组腺病毒（AdFIX），并随时间监测血浆FIX水平。用这两种试剂处理均显著延长了转基因表达。这种持续性伴随着抗腺病毒（抗Ad）IgG的抑制，以及体外再次暴露于病毒颗粒的脾淋巴细胞中IL-10和IFN-γ产生的减少。为了测试对再次给药的影响，给小鼠首次输注编码细菌β-半乳糖苷酶的重组腺病毒（Adβgal），然后在第24天和第63天进行AdFIX的二次和三次输注。接受MR-1的小鼠在第24天的抗Ad水平低至无法检测到，并且发生了有效的转导。此外，这些小鼠中的FIX水平持续存在，在第63天有40%的FIX保留，而未处理的对照小鼠中FIX迅速丧失。在第63天，可忽略不计的抗Ad水平的持续与成功的三次转导相关。这些结果表明，巨噬细胞清除和CD40配体阻断均抑制对重组腺病毒的免疫反应，以减缓转基因表达的下降，而只有CD40配体阻断充分抑制抗Ad抗体的产生，从而允许向肝脏再次给药。
