Immunotherapy Ameliorate Neurological Deficits in Encephalitis

免疫疗法可改善脑炎的神经功能缺陷

基本信息

批准号：
8771312
负责人：
EDOUARD M CANTIN
金额：
$ 25.38万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-05-01 至 2016-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8771312
关键词：
Acute Acyclovir Adult Affect Affinity Aftercare Alzheimer&apos s Disease Amygdaloid structure Anti-Inflammatory Agents Anti-inflammatory Antiviral Agents Antiviral Therapy Area Behavior Bioinformatics Biological Biological Markers Brain Brain region Caring Cell Nucleus Central Nervous System Infections Child Clinical Cognitive Combined Modality Therapy Cytopathology Data Development Diagnosis Diagnostic Procedure Disease Emotions Encephalitis Goals Herpesvirus 1 Human Hypothalamic structure Immunotherapeutic agent Immunotherapy Impairment Incidence Independent Living Infection Infection prevention Inflammation Inflammatory Inflammatory Infiltrate Inflammatory Response Intravenous Immunoglobulins Latent Virus Learning Disabilities Lesion Licensing Limbic System Medial Memory Memory impairment Modeling Motor Mus Nervous System Physiology Neuraxis Neurodegenerative Disorders Neurologic Neurological outcome Neurological status Neurons Newborn Infant Outcome Pathology Pathway Analysis Pathway interactions Patients Pharmaceutical Preparations Population Preparation Proteins Proteomics Reproducibility Resolution Risk Risk Factors Route Running Sampling Seeds Sensory Serum Serum Proteins Simplexvirus Smell Perception Specificity Survivors Temporal Lobe Testing Thalamic structure Time Trigeminal System Trigeminal nerve structure Validation Viral Encephalitis Viral load measurement Virus West Nile virus clinical efficacy combinatorial disability expectation immunopathology improved latent infection man mortality mouse model neonate neurobehavioral test olfactory bulb permissiveness piriform cortex prevent public health relevance response

项目摘要

DESCRIPTION (provided by applicant): Herpes Simplex Virus type 1 (HSV) infections are ubiquitous in man with >85% of the global adult population being latently infected. HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis resulting from primary infections in neonates or reactivated latent infections in adults. Although, significant advances i diagnosis of HSE and development of potent antiviral drugs have significantly reduced mortality, most survivors (>60%) suffer severe neurological complications that preclude them returning to independent living; prospects for children who develop cognitive and learning disabilities are particularly bleak. Anatomically and functionally long-term damage from HSE is usually confined to the limbic system in man. Intranasal inoculation of mice seeds infection in this same limbic brain region that supports a variety of functions including memory, emotion, behavior and olfaction. Importantly, inflammatory lesions and prolonged inflammation in the limbic region has been correlated with memory impairment in untreated mice surviving HSV infection. Thus this mouse model is ideally suited for exploring treatments that could ameliorate long-term neurological deficits afflicting most patients surviving HSE. We have shown definitively that the pathology underlying HSE results from exaggerated CNS inflammatory responses rather than virus-induced cytopathology. In contrast to the antiviral drug acyclovir, that blocks only HSV replication, intravenous immunoglobulins (IVIG) exert potent anti-inflammatory and antiviral effects to prevent HSE. We propose neurobehavioral testing of mice surviving HSV brain infection to validate the hypothesis in Specific Aim 1 that combinatorial antiviral-immunotherapy (ACV+IVIG), compared ACV monotherapy, will reduce CNS immunopathology and thereby result in improved neurological outcomes for HSV infected mice. In Specific Aim 2, the goal is to use serum proteomic profiles to identify protein signatures that are correlated with beneficial anti-inflammatory responses compared to deleterious proinflammatory responses in infected mice receiving combinatorial ACV-IVIG or ACV monotherapy, respectively. Bioinformatic, statistical and Ingenuity Pathway Analysis (IPA) will be used to identify proteins upregulated in IVIG treated mice that converge on pathway(s) implicated in anti-inflammatory responses and thus represent candidate biomarkers. After further testing and validation these biomarkers would be clinically useful for predicting desirable anti-inflammatory, as compared to undesirable proinflammatory responses in patients treated with an antiviral-immunotherapy cocktail incorporating IVIG as an anti-inflammatory and immunomodulatory drug.

描述（由申请人提供）：单纯疱疹病毒1型（HSV）感染无处不在，> 85％的全球成年人群被延迟感染。 HSV脑炎（HSE）是最普遍的零星病毒性脑炎，是由于新生儿的主要感染或成人重新激活的潜在感染而引起的。尽管I对HSE的诊断和有效抗病毒药的发展的重大进展显着降低了死亡率，但大多数幸存者（> 60％）遭受了严重的神经系统并发症，排除了他们恢复独立生活；发展认知和学习障碍的儿童的前景特别黯淡。 HSE在解剖学和功能上长期损害通常仅限于人类的边缘系统。在同一边缘大脑区域中，小鼠种子感染的鼻内接种，支持多种功能，包括记忆，情感，行为和嗅觉。重要的是，边缘区域的炎症病变和长时间的炎症与存活HSV感染的未处理小鼠的记忆障碍有关。因此，该小鼠模型非常适合探索可以改善长期神经缺陷的治疗方法，使大多数存活的HSE患者都折磨。我们已经确定地表明，HSE的病理学是由夸张的中枢神经系统炎症反应而不是病毒诱导的细胞病理学导致的。与仅阻塞HSV复制的抗病毒药物阿西洛韦相反，静脉免疫球蛋白（IVIG）发挥有效的抗炎和抗病毒作用来防止HSE。我们提出了生存HSV脑感染的小鼠的神经行为测试，以验证特定目标1中的假设，即联合抗病毒免疫疗法（ACV+IVIG）比较了ACV单一疗法，将减少CNS免疫病理学，从而减少改善的HSV感染小鼠神经学的神经系统疾病。在特定目标2中，目标是使用血清蛋白质组学特征来鉴定与有害抗炎反应相关的蛋白质特征，与分别接受组合ACV-IVIG或ACV组合疗法的受感染小鼠的有害促炎性反应相比。生物信息学，统计和Ingenuity途径分析（IPA）将用于识别在IVIG处理的小鼠中上调的蛋白质，这些蛋白会收敛于与抗炎反应有关的途径上，因此代表候选生物标志物。在进行进一步的测试和验证之后，这些生物标志物对于预测所需的抗炎作用将在临床上有用，与用抗病毒免疫疗法鸡尾酒治疗的患者相比，将IVIG掺入IVIG作为抗炎和免疫调节药物。