Neuroprotective Vaccination for Parkinson's Disease

帕金森病的神经保护性疫苗

• 批准号: 6909931
• 负责人: R Lee Mosley
• 金额: $ 15.36万
• 依托单位: UNIVERSITY OF NEBRASKA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6909931
• 关键词: B lymphocyte; Parkinson' s disease; T lymphocyte; colony stimulating factor; copolymer I; disease /disorder model; dopamine; dopamine receptor; immune response; immunomodulators; laboratory mouse; mass spectrometry; methylphenyltetrahydropyridine; natural killer cells; neural degeneration; neuroprotectants; nonhuman therapy evaluation; protein sequence; vaccine development; vaccine evaluation

DESCRIPTION (provided by applicant): Microglia inflammation contributes, in significant measure, to the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) during idiopathic Parkinson's disease (PD). Attenuation of such inflammation could attenuate disease. To this end we show that microglial deactivation responses, induced by vaccination, in 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropyridine (MPTP) intoxicated mice improves dopaminergic neuronal survival. This was achieved by adoptively transferring spleen cells from copolymer-1 (Cop-1) immunized mice to MPTP-treated recipients. Spleen cells from ovalbumin (OVA) injected mice failed to affect neuronal protection. Thus, our preliminary works show that protection from dopaminergic neurodegeneration can be achieved by adaptive immunity with T cells specific for Cop-1. Based on response kinetics, antigen specificity, and functional adaptive T cell immune responses, we predict that the mechanism(s) of neuroprotective immunity can be realized and could provide novel treatment strategies for human disease. Our hypothesis posits that protection from dopaminergic neurodegeneration by Cop-1 vaccination is generated through immune cell-mediated mechanisms with specificity for Cop-1 peptides and self-antigens. To investigate this we will adoptively transfer T lymphocytes, B cells and monocytes from Cop-1 immunized mice into MPTP-treated animals. Neuroprotection will be assessed by numbers of dopaminergic neurons, neurotransmitter levels, and neuronal metabolites by magnetic resonance spectroscopic imaging (MRSI). Immune cell populations, proven relevant to neuroprotection will be evaluated for the expression of gene products that are cell population specific as candidates for neuroprotection. Genetic fingerprint analysis will include cDNA microarray analysis and proteomics. This approach takes advantage of an integrated and well-established research program within the Center for Neurovirology and Neurodegenerative Disorders and builds upon research activities in PD supported previously through private donations. These approaches could prove useful for treatment of human PD.

描述（由申请人提供）：小胶质细胞炎症在很大程度上导致了特发性帕金森氏病（PD）期间的底虫PARS Comcacta（SNPC）中多巴胺能神经元的丧失。这种炎症的衰减会减轻疾病。为此，我们表明，在1-甲基-4-苯基-1、2、2、3、6-四氢吡啶（MPTP）陶醉的小鼠中，由疫苗接种诱导的小胶质细胞失活反应可改善多巴胺能神经元的生存。这是通过从共聚物1（COP-1）免疫小鼠转移到MPTP处理的受体中来实现的。来自卵巢蛋白（OVA）注射小鼠的脾细胞未影响神经元保护。因此，我们的初步工作表明，可以通过对COP-1特异性的T细胞的自适应免疫来保护对多巴胺能神经退行性的保护。根据反应动力学，抗原特异性和功能适应性T细胞免疫反应，我们预测可以实现神经保护免疫的机制，并可以为人类疾病提供新颖的治疗策略。我们的假设认为，通过具有特异性的COP-1肽和自我抗原特异性的免疫细胞介导的机制，通过COP-1疫苗接种来保护多巴胺能神经退行性。为了调查这一点，我们将从COP-1免疫小鼠中传递T淋巴细胞，B细胞和单核细胞转移到MPTP处理的动物中。神经保护将通过多巴胺能神经元，神经递质水平和神经元代谢产物的数量评估，并通过磁共振光谱成像（MRSI）评估。将评估与神经保护作用相关的免疫细胞群体的表达，这些基因产物的表达是细胞群特有的作为神经保护的候选者。遗传指纹分析将包括cDNA微阵列分析和蛋白质组学。这种方法利用了神经病毒学和神经退行性疾病中心内的一体综合且建立了良好的研究计划，并基于以前通过私人捐赠支持的PD研究活动。这些方法可用于治疗人类PD。