Kim Hong-Duck, Jin Jing-Ji, Maxwell J Adam, Fukuchi Ken-ichiro
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, P.O. Box 1649, Peoria, IL 61656, USA.
Immunol Lett. 2007 Sep 15;112(1):30-8. doi: 10.1016/j.imlet.2007.06.006. Epub 2007 Jul 23.
Accumulation of aggregated amyloid beta-protein (Abeta) in the brain is thought to be the initiating event leading to neurodegeneration and dementia in Alzheimer's disease (AD). Therefore, therapeutic strategies that clear accumulated Abeta and/or prevent Abeta production and its aggregation are predicted to be effective against AD. Immunization of AD mouse models with synthetic Abeta prevented or reduced Abeta load in the brain and ameliorated their memory and learning deficits. The clinical trials of Abeta immunization elicited immune responses in only 20% of AD patients and caused T-lymphocyte meningoencephalitis in 6% of AD patients. In attempting to develop safer vaccines, we previously demonstrated that an adenovirus vector, AdPEDI-(Abeta1-6)11, which encodes 11 tandem repeats of Abeta1-6 can induce anti-inflammatory Th2 immune responses in mice. Here, we investigated whether a DNA prime-adenovirus boost regimen could elicit a more robust Th2 response using AdPEDI-(Abeta1-6)11 and a DNA plasmid encoding the same antigen. All mice (n=7) subjected to the DNA prime-adenovirus boost regimen were positive for anti-Abeta antibody, while, out of 7 mice immunized with only AdPEDI-(Abeta1-6)11, four mice developed anti-Abeta antibody. Anti-Abeta titers were indiscernible in mice (n=7) vaccinated with only DNA plasmid. The mean anti-Abeta titer induced by the DNA prime-adenovirus boost regimen was approximately 7-fold greater than that by AdPEDI-(Abeta1-6)11 alone. Furthermore, anti-Abeta antibodies induced by the DNA prime-adenovirus boost regimen were predominantly of the IgG1 isotype. These results indicate that the DNA prime-adenovirus boost regimen can enhance Th2-biased responses with AdPEDI-(Abeta1-6)11 in mice and suggest that heterologous prime-boost strategies may make AD immunotherapy more effective in reducing accumulated Abeta.
大脑中聚集的淀粉样β蛋白（Aβ）的积累被认为是导致阿尔茨海默病（AD）神经退行性变和痴呆的起始事件。因此，清除积累的Aβ和/或预防Aβ产生及其聚集的治疗策略预计对AD有效。用合成Aβ对AD小鼠模型进行免疫可预防或减少大脑中的Aβ负荷，并改善其记忆和学习缺陷。Aβ免疫的临床试验仅在20%的AD患者中引发了免疫反应，并在6%的AD患者中导致了T淋巴细胞性脑膜脑炎。在试图开发更安全的疫苗时，我们之前证明了一种腺病毒载体AdPEDI-(Aβ1-6)11，它编码Aβ1-6的11个串联重复序列，可在小鼠中诱导抗炎性Th2免疫反应。在这里，我们研究了DNA初免-腺病毒加强方案是否能使用AdPEDI-(Aβ1-6)11和编码相同抗原的DNA质粒引发更强的Th2反应。接受DNA初免-腺病毒加强方案的所有小鼠（n=7）抗Aβ抗体呈阳性，而在仅用AdPEDI-(Aβ1-6)11免疫的7只小鼠中，有4只小鼠产生了抗Aβ抗体。仅接种DNA质粒的小鼠（n=7）中抗Aβ滴度无法辨别。DNA初免-腺病毒加强方案诱导的平均抗Aβ滴度比单独使用AdPEDI-(Aβ1-6)11诱导的滴度大约高7倍。此外，DNA初免-腺病毒加强方案诱导的抗Aβ抗体主要是IgG1同种型。这些结果表明，DNA初免-腺病毒加强方案可以增强AdPEDI-(Aβ1-6)11在小鼠中偏向Th2的反应，并表明异源初免-加强策略可能使AD免疫治疗在减少积累的Aβ方面更有效。
