Department of Neurosurgery, Tianjin First Center Hospital, Tianjin, China.
J Neuroimmune Pharmacol. 2012 Sep;7(3):640-55. doi: 10.1007/s11481-012-9371-2. Epub 2012 Jun 9.
Despite FDA suspension of Elan's AN-1792 amyloid beta (Aβ) vaccine in phase IIb clinical trials, the implications of this study are the guiding principles for contemporary anti-Aβ immunotherapy against Alzheimer's disease (AD). AN-1792 showed promising results with regards to Aβ clearance and cognitive function improvement, but also exhibited an increased risk of Th1 mediated meningoencephalitis. As such, vaccine development has continued with an emphasis on eliciting a notable anti-Aβ antibody titer, while avoiding the unwanted Th1 pro-inflammatory response. Previously, we published the first report of an Aβ sensitized dendritic cell vaccine as a therapeutic treatment for AD in BALB/c mice. Our vaccine elicited an anti-Aβ titer, with indications that a Th1 response was not present. This study is the first to investigate the efficacy and safety of our dendritic cell vaccine for the prevention of AD in transgenic mouse models (PDAPP) for AD. We also used Immunohistochemistry to characterize the involvement of LXR, ABCA1, and CD45 in order to gain insight into the potential mechanisms through which this vaccine may provide benefit. The results indicate that (1) the use of mutant Aβ1-42 sensitized dendritic cell vaccine results in durable antibody production, (2) the vaccine provides significant benefits with regards to cognitive function without the global (Th1) inflammation seen in prior Aβ vaccines, (3) histological studies showed an overall decrease in Aβ burden, with an increase in LXR, ABCA1, and CD45, and (4) the beneficial results of our DC vaccine may be due to the LXR/ABCA1 pathway. In the future, mutant Aβ sensitized dendritic cell vaccines could be an efficacious and safe method for the prevention or treatment of AD that circumvents problems associated with traditional anti-Aβ vaccines.
尽管美国食品药品监督管理局（FDA）暂停了 Elan 的 AN-1792 淀粉样蛋白β（Aβ）疫苗的 IIb 期临床试验，但这项研究的意义为当代针对阿尔茨海默病（AD）的抗 Aβ 免疫疗法提供了指导原则。AN-1792 在 Aβ清除和认知功能改善方面显示出了良好的效果，但也表现出了 Th1 介导的脑膜脑炎风险增加。因此，疫苗的开发继续强调引起显著的抗 Aβ 抗体滴度，同时避免不受欢迎的 Th1 促炎反应。此前，我们发表了第一篇关于 Aβ致敏树突状细胞疫苗作为 AD 治疗方法的报告，在 BALB/c 小鼠中进行了 AD 治疗。我们的疫苗引起了抗 Aβ 滴度，表明不存在 Th1 反应。这项研究首次调查了我们的树突状细胞疫苗在 AD 转基因小鼠模型（PDAPP）中预防 AD 的疗效和安全性。我们还使用免疫组织化学来描述 LXR、ABCA1 和 CD45 的参与情况，以便深入了解该疫苗可能提供益处的潜在机制。结果表明：（1）使用突变 Aβ1-42 致敏的树突状细胞疫苗可导致持久的抗体产生；（2）疫苗在认知功能方面提供了显著的益处，而没有先前 Aβ 疫苗所见的全身性（Th1）炎症；（3）组织学研究表明 Aβ 负荷总体减少，LXR、ABCA1 和 CD45 增加；（4）我们的 DC 疫苗的有益结果可能归因于 LXR/ABCA1 途径。在未来，突变 Aβ 致敏的树突状细胞疫苗可能是一种有效和安全的预防或治疗 AD 的方法，可以规避与传统抗 Aβ 疫苗相关的问题。
