Burchell Jennifer T, Panegyres Peter K
Neurodegenerative Disorders Research Pty Ltd, West Perth, Western Australia, Australia.
Immunotargets Ther. 2016 Jun 16;5:57-68. doi: 10.2147/ITT.S64795. eCollection 2016.
Transmissible spongiform encephathalopathies or prion diseases are a group of neurological disorders characterized by neuronal loss, spongiform degeneration, and activation of astrocytes or microglia. These diseases affect humans and animals with an extremely high prevalence in some species such as deer and elk in North America. Although rare in humans, they result in a devastatingly swift neurological progression with dementia and ataxia. Patients usually die within a year of diagnosis. Prion diseases are familial, sporadic, iatrogenic, or transmissible. Human prion diseases include Kuru, sporadic, iatrogenic, and familial forms of Creutzfeldt-Jakob disease, variant Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, and fatal familial insomnia. The causative agent is a misfolded version of the physiological prion protein called PrP(Sc) in the brain. There are a number of therapeutic options currently under investigation. A number of small molecules have had some success in delaying disease progression in animal models and mixed results in clinical trials, including pentosan polysulfate, quinacrine, and amphotericin B. More promisingly, immunotherapy has reported success in vitro and in vivo in animal studies and clinical trials. The three main branches of immunotherapy research are focus on antibody vaccines, dendritic cell vaccines, and adoptive transfer of physiological prion protein-specific CD4(+) T-lymphocytes. Vaccines utilizing antibodies generally target disease-specific epitopes that are only exposed in the misfolded PrP(Sc) conformation. Vaccines utilizing antigen-loaded dendritic cell have the ability to bypass immune tolerance and prime CD4(+) cells to initiate an immune response. Adoptive transfer of CD4(+) T-cells is another promising target as this cell type can orchestrate the adaptive immune response. Although more research into mechanisms and safety is required, these immunotherapies offer novel therapeutic targets for prion diseases.
传染性海绵状脑病或朊病毒病是一组神经疾病，其特征为神经元丧失、海绵状变性以及星形胶质细胞或小胶质细胞激活。这些疾病会影响人类和动物，在北美某些物种如鹿和麋鹿中患病率极高。虽然在人类中罕见，但它们会导致伴有痴呆和共济失调的极其迅速的神经病变。患者通常在确诊后一年内死亡。朊病毒病有家族性、散发性、医源性或传染性。人类朊病毒病包括库鲁病、散发性、医源性和家族性克雅氏病、变异型克雅氏病、格斯特曼-施特劳斯勒-谢inker病以及致死性家族性失眠症。致病因子是大脑中一种名为PrP(Sc)的生理朊病毒蛋白的错误折叠形式。目前有多种治疗方案正在研究中。一些小分子在动物模型中成功延缓了疾病进展，但在临床试验中结果不一，包括戊聚糖多硫酸盐、氯喹和两性霉素B。更有前景的是，免疫疗法在动物研究和临床试验的体外及体内均有成功报道。免疫疗法研究的三个主要分支聚焦于抗体疫苗、树突状细胞疫苗以及生理朊病毒蛋白特异性CD4(+) T淋巴细胞的过继转移。利用抗体的疫苗通常靶向仅在错误折叠的PrP(Sc)构象中暴露的疾病特异性表位。利用负载抗原的树突状细胞的疫苗有能力绕过免疫耐受并激活CD4(+)细胞以引发免疫反应。CD4(+) T细胞的过继转移是另一个有前景的靶点，因为这种细胞类型可协调适应性免疫反应。尽管还需要对机制和安全性进行更多研究，但这些免疫疗法为朊病毒病提供了新的治疗靶点。
