High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice
High titers of mucosal and systemic anti-PrP antibodies abrogate oral prion infection in mucosal-vaccinated mice
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DOI：
10.1016/j.neuroscience.2008.02.051
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发表时间：
2008-05-15
期刊：
影响因子：
3.3
通讯作者：
Wisniewski, T.
中科院分区：
文献类型：
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作者：
Goni, F.;Prelli, F.;Wisniewski, T.
在动物和人群中发生了与口服接触朊病毒剂有关的重大朊病毒疾病暴发。这些疾病与正常蛋白PrPc （C表示细胞蛋白）的构象变化有关，PrPsc （Sc表示痒病蛋白）具有毒性和传染性。目前还没有有效的治疗方法。某些形式的朊病毒疾病被认为是通过口服PrPsc传播的，如慢性消耗性疾病和变异型克雅氏病。在野生型动物中获得主动免疫的尝试受到对PrP的自身耐受性和潜在毒性的阻碍。先前，我们证明了通过口服接种在减毒沙门氏菌载体中表达的PrP蛋白，可以克服耐受性并获得特异性抗PrP抗体反应。过去的这项研究表明，30%接种过疫苗的动物在接种后350多天内没有发病。在本研究中，我们优化了疫苗接种方案，并将接种疫苗的小鼠分为低免疫应答组和高免疫应答组，然后口服PrPsc痒病菌株139A。这些方法的改进显著改善了治疗效果。在攻击前，100%具有高黏膜抗PrP滴度免疫球蛋白（Ig） a和高全身IgG滴度的小鼠在400天内仍然没有PrP感染症状（对数秩检验p < 0.0001与假对照组相比）。经Western blot和组织学检查，这些存活的临床无症状小鼠的脑组织没有PrPsc感染。这些有希望的发现表明，有效的粘膜疫苗接种是克服对PrP的耐受性和通过口服途径预防朊病毒感染的可行和有用的方法(c) 2008 IBRO。Elsevier Ltd.出版。版权所有。
Significant outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrPc (C for cellular), to a toxic and infectious form, PrPsc (Sc for scrapie). None of the prionoses currently have an effective treatment. Some forms of prion disease are thought to be spread by oral ingestion of PrPsc, such as chronic wasting disease and variant Creutzfeldt-Jakob disease. Attempts to obtain an active immunization in wild-type animals have been hampered by auto-tolerance to PrP and potential toxicity. Previously, we demonstrated that it is possible to overcome tolerance and obtain a specific anti-PrP antibody response by oral inoculation of the PrP protein expressed in an attenuated Salmonella vector. This past study showed that 30% of vaccinated animals were free of disease more than 350 days post-challenge. In the current study we have both optimized the vaccination protocol and divided the vaccinated mice into low and high immune responder groups prior to oral challenge with PrPsc scrapie strain 139A. These methodological refinements led to a significantly improved therapeutic response. 100% of mice with a high mucosal anti-PrP titer immunoglobulin (Ig) A and a high systemic IgG titer, prior to challenge, remained without symptoms of PrP infection at 400 days (log-rank testP < 0.0001 versus sham controls). The brains from these surviving clinically asymptomatic mice were free of PrPsc infection by Western blot and histological examination. These promising findings suggest that effective mucosal vaccination is a feasible and useful method for overcoming tolerance to PrP and preventing prion infection via an oral route (c) 2008 IBRO. Published by Elsevier Ltd. All rights reserved.