Brody David L, Holtzman David M
Department of Neurology, Developmental Biology, Alzheimer's Disease Research Center, and Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, Missouri 63110, USA.
Annu Rev Neurosci. 2008;31:175-93. doi: 10.1146/annurev.neuro.31.060407.125529.
Immunotherapeutic strategies to combat neurodegenerative disorders have galvanized the scientific community since the first dramatic successes in mouse models recreating aspects of Alzheimer disease (AD) were reported. However, initial human trials of active amyloid-beta (Abeta) vaccination were halted early because of a serious safety issue: meningoencephalitis in 6% of subjects. Nonetheless, some encouraging preliminary data were obtained, and rapid progress has been made toward developing alternative, possibly safer active and passive immunotherapeutic approaches for several neurodegenerative conditions. Many of these are currently in human trials for AD. Despite these advances, our understanding of the essential mechanisms underlying the effects seen in preclinical models and human subjects is still incomplete. Antibody-induced phagocytosis of pathological protein deposits, direct antibody-mediated disruption of aggregates, neutralization of toxic soluble proteins, a shift in equilibrium toward efflux of specific proteins from the brain, cell-mediated immune responses, and other mechanisms may all play roles depending on the specific immunotherapeutic scenario.
自从在重现阿尔茨海默病（AD）某些方面的小鼠模型中首次取得显著成功以来，对抗神经退行性疾病的免疫治疗策略激发了科学界的兴趣。然而，活性β-淀粉样蛋白（Aβ）疫苗接种的初步人体试验因一个严重的安全问题而提前终止：6%的受试者出现了脑膜脑炎。尽管如此，还是获得了一些令人鼓舞的初步数据，并且在为几种神经退行性疾病开发替代的、可能更安全的主动和被动免疫治疗方法方面取得了快速进展。其中许多方法目前正在进行AD的人体试验。尽管取得了这些进展，但我们对临床前模型和人类受试者中所见效应的基本机制的理解仍然不完整。抗体诱导的病理性蛋白质沉积物的吞噬作用、抗体直接介导的聚集体破坏、有毒可溶性蛋白质的中和、平衡向特定蛋白质从大脑流出的方向转变、细胞介导的免疫反应以及其他机制可能都根据具体的免疫治疗情况发挥作用。
