Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.
Transcriptional dysregulation of inflammatory/immune pathways after active vaccination against Huntington's disease.
复制标题
积极接种亨廷顿病疫苗后炎症/免疫途径的转录失调。
DOI：
10.1093/hmg/ddv335
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发表时间：
2015
影响因子：
3.5
通讯作者：
Messer,Anne
中科院分区：
文献类型：
--
作者：
Ramsingh,ArleneI;Manley,Kevin;Rong,Yinghui;Reilly,Andrew;Messer,Anne
免疫疗法，无论是主动的还是被动的，越来越被认为是治疗多种疾病的有力方法，包括阿尔茨海默病和帕金森病。亨廷顿氏病（HD）是一种常染色体显性遗传病，由亨廷顿蛋白（HTT）蛋白的错误折叠与扩大的聚谷氨酰胺束引发，也可能受益于这种方法。个体可以在疾病的早期阶段进行基因鉴定，除了大脑外，还可以针对外周组织的治疗可能会有特别的好处。在这项主动疫苗接种研究中，我们首先使用片段（R6/1）和敲入（zQ175）模型，检查了一系列肽、蛋白质和DNA质粒免疫方案的安全性和免疫原性。没有发现安全问题。最强和最均匀的免疫应答是三种非重叠的httexon1编码肽的组合，与KLH结合，与明矾佐剂一起递送。通过基因枪传递的N586-82Q质粒也显示出ELISA应答，主要在zQ175菌株中，但与野生型对照相比，HD具有更多的可变性，且应答较弱。三肽免疫组脾脏的转录组分析显示了大量的hd特异性差异，包括与先天免疫应答相关的基因的差异激活，调节因子对基因表达的负反馈控制缺失，先天免疫应答的时间失调以及与记忆T细胞应答相关的基因的转录抑制。这些研究强调了免疫治疗和HD疾病管理的关键问题。
Immunotherapy, both active and passive, is increasingly recognized as a powerful approach to a wide range of diseases, including Alzheimer's and Parkinson's. Huntington's disease (HD), an autosomal dominant disorder triggered by misfolding of huntingtin (HTT) protein with an expanded polyglutamine tract, could also benefit from this approach. Individuals can be identified genetically at the earliest stages of disease, and there may be particular benefits to a therapy that can target peripheral tissues in addition to brain. In this active vaccination study, we first examined safety and immunogenicity for a broad series of peptide, protein and DNA plasmid immunization protocols, using fragment (R6/1), and knock-in (zQ175) models. No safety issues were found. The strongest and most uniform immune response was to a combination of three non-overlappingHTTExon1 coded peptides, conjugated to KLH, delivered with alum adjuvant. An N586-82Q plasmid, delivered via gene gun, also showed ELISA responses, mainly in the zQ175 strain, but with more variability, and less robust responses in HD compared with wild-type controls. Transcriptome profiling of spleens from the triple peptide-immunized cohort showed substantial HD-specific differences including differential activation of genes associated with innate immune responses, absence of negative feedback control of gene expression by regulators, a temporal dysregulation of innate immune responses and transcriptional repression of genes associated with memory T cell responses. These studies highlight critical issues for immunotherapy and HD disease management in general.