Antibody response and plasma Abeta1-40 levels in young Microcebus murinus primates immunized with Abeta1-42 and its derivatives.
Antibody response and plasma Abeta1-40 levels in young Microcebus murinus primates immunized with Abeta1-42 and its derivatives.
复制标题
用 Abeta1-42 及其衍生物免疫的年轻 Microcebus murinus 灵长类动物的抗体反应和血浆 Abeta1-40 水平。
DOI：
10.1016/j.vaccine.2008.12.012
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发表时间：
2009
期刊：
影响因子：
5.5
通讯作者：
Mestre-Francés,Nadine
中科院分区：
文献类型：
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作者：
Trouche,StéphanieG;Asuni,Ayodeji;Rouland,Sylvie;Wisniewski,Thomas;Frangione,Blas;Verdier,Jean-Michel;Sigurdsson,EinarM;Mestre-Francés,Nadine
为了提高Aβ靶向免疫治疗的安全性，我们一直在开发Aβ衍生物疫苗。与Aβ相比，我们的Aβ同系物的直接毒性较小，并产生改良的免疫反应。在广泛的小鼠研究中，我们所有的疫苗都提高了转基因小鼠的认知能力，同时引发了不同的免疫反应，并在不同程度上减少了大脑淀粉样蛋白的负担。在我们继续在小鼠中表征这些疫苗的同时，为了准备在老年灵长类动物中的研究和人体试验，我们评估了它们在年轻狐猴灵长类动物（n=25）中的效果，这些灵长类动物随着年龄的增长会产生Aβ斑块和tau聚集体，如在阿尔茨海默病中所见。在灵长类动物中，与明矾佐剂一起给予的所有肽均引发中度至稳健的抗A β IgM应答。Aβ1-42、K6 A β1-30和K6 A β1-30[E18 E19]导致较高的抗A β IgG应答，而Aβ1-30[E18 E19]产生较弱的可变IgG滴度。值得注意的是，第3次免疫后22周，衍生物接种灵长类动物的IgM和IgG水平与免疫前值相似，而Aβ1-42处理灵长类动物保持中等IgG滴度。识别Aβ1-40的抗体的增加通常与血浆中Aβ1-40的增加相关，这表明抗体在体内与Aβ结合。有趣的是，注射后观察到显著的一过性体重增加（K6 A β1-30、Aβ1-30[E18 E19]和Aβ1-42给药）或相同方向的趋势（K6 A β1-30[E18 E19]给药，佐剂对照）。基于这些发现，我们选择K6 A β1-30用于老年灵长类动物的免疫接种，因为与其他Aβ衍生物相比，对该疫苗的抗体应答变化较小。我们目前的研究结果表明，我们的大多数Aβ衍生物在灵长类动物中引发了大量的抗体应答，重要的是，这种作用是可逆的，这增强了我们方法的安全性。
We have been developing Aβ derivative vaccines with the objective to improve the safety of Aβ targeting immunotherapy. Our Aβ homologs are designed to have less direct toxicity and to produce a modified immune response compared to Aβ. In extensive mouse studies, all our vaccines have improved cognition in transgenic mice while eliciting different immune responses and reducing brain amyloid burden to a variable degree. While we are continuing to characterize these vaccines in mice, in preparation for studies in old primates and for human trials we assessed their effect in young lemur primates (n=25) that with age develop Aβ plaques and tau aggregates as seen in Alzheimer's disease. In the primates, all the peptides administered with alum adjuvant elicited a moderate to robust anti-Aβ IgM response. Aβ1-42, K6Aβ1-30 and K6Aβ1-30[E18E19] resulted in a high anti-Aβ IgG response, whereas Aβ1-30[E18E19] produced a weaker more variable IgG titer. Notably, 22 weeks after the 3rd immunization, IgM and IgG levels in derivative-vaccinated primates were similar to preimmune values whereas Aβ1-42 treated primates maintained a moderate IgG titer. The increase in antibodies that recognized Aβ1-40 often correlated with increase in Aβ1-40 in plasma, which suggests that the antibodies were binding to Aβ in vivo. Interestingly, significant transient weight gain was observed (K6Aβ1-30-, Aβ1-30[E18E19]- and Aβ1-42-treated) or a trend in the same direction (K6Aβ1-30[E18E19]-treated, adjuvant controls) following the injections. Based on these findings, we have chosen K6Aβ1-30 for immunizations in old primates as the antibody response to this vaccine was less variable compared to other Aβ derivatives. Our present findings indicate that most of our Aβ derivatives elicit a substantial antibody response in primates, and importantly this effect is reversible which enhances the safety profile of our approach.