Kim Hong-Duck, Tahara Kazuki, Maxwell J Adam, Lalonde Robert, Fukuiwa Tatsuya, Fujihashi Kohtaro, Van Kampen Kent R, Kong Fan-Kun, Tang De-chu C, Fukuchi Ken-ichiro
Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, PO Box 1649, Peoria, IL 61656, USA.
J Gene Med. 2007 Feb;9(2):88-98. doi: 10.1002/jgm.993.
One of the pathological hallmarks of Alzheimer's disease (AD) is deposits of amyloid beta-peptide (Abeta) in neuritic plaques and cerebral vessels. Immunization of AD mouse models with Abeta reduces Abeta deposits and improves memory and learning deficits. Because recent clinical trials of immunization with Abeta were halted due to brain inflammation that was presumably induced by a T-cell-mediated autoimmune response, vaccination modalities that elicit predominantly humoral immune responses are currently being developed.
We have nasally immunized a young AD mouse model with an adenovirus vector encoding 11 tandem repeats of Abeta1-6 fused to the receptor-binding domain (Ia) of Pseudomonas exotoxin A (PEDI), AdPEDI-(Abeta1-6)(11), in order to evaluate the efficacy of the vector in preventing Abeta deposits in the brain. We also have investigated immune responses of mice to AdPEDI-(Abeta1-6)(11).
Nasal immunization of an AD mouse model with AdPEDI-(Abeta1-6)(11) elicited a predominant IgG1 response and reduced Abeta load in the brain. The plasma IL-10 level in the AD mouse model was upregulated after immunization and, upon the stimulation with PEDI-(Abeta1-6)(11), marked IL-10 responses were found in splenic CD4(+) T cells from C57BL/6 mice that had been immunized with AdPEDI-(Abeta1-6)(11).
These results suggest that the induction of Th2-biased responses with AdPEDI-(Abeta1-6)(11) in mice is mediated in part through the upregulation of IL-10, which inhibits activation of dendritic cells that dictate the induction of Th1 cells.
阿尔茨海默病（AD）的病理特征之一是淀粉样β肽（Aβ）在神经炎性斑块和脑血管中沉积。用Aβ免疫AD小鼠模型可减少Aβ沉积，并改善记忆和学习缺陷。由于最近Aβ免疫的临床试验因可能由T细胞介导的自身免疫反应引起的脑部炎症而停止，目前正在开发主要引发体液免疫反应的疫苗接种方式。
我们用编码与外毒素A（PEDI）的受体结合域（Ia）融合的Aβ1-6的11个串联重复序列的腺病毒载体，即AdPEDI-(Aβ1-6)(11)，对年轻的AD小鼠模型进行鼻内免疫，以评估该载体在预防脑中Aβ沉积方面的功效。我们还研究了小鼠对AdPEDI-(Aβ1-6)(11)的免疫反应。
用AdPEDI-(Aβ1-6)(11)对AD小鼠模型进行鼻内免疫引发了主要的IgG1反应，并降低了脑中的Aβ负荷。免疫后AD小鼠模型的血浆IL-10水平上调，在用PEDI-(Aβ1-6)(11)刺激后，在已用AdPEDI-(Aβ1-6)(11)免疫的C57BL/6小鼠的脾CD4(+) T细胞中发现了明显的IL-10反应。
这些结果表明，在小鼠中用AdPEDI-(Aβ1-6)(11)诱导偏向Th2的反应部分是通过IL-10的上调介导的，IL-10抑制了决定Th1细胞诱导的树突状细胞的激活。
