Chemokine IP-10 and Viral-Induced Demyelination

趋化因子 IP-10 和病毒引起的脱髓鞘

基本信息

批准号：
6657924
负责人：
Thomas E Lane
金额：
$ 18.27万
依托单位：
UNIVERSITY OF SOUTHERN CALIFORNIA
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-04-01 至 2008-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6657924
关键词：
IP 10 protein T lymphocyte astrocytes cell migration cytokine encephalomyelitis helper T lymphocyte inflammation laboratory mouse latent virus infection macrophage molecular pathology murine hepatitis virus neurotropic virus neutralizing antibody viral myelinopathy

项目摘要

Infection of susceptible mice with mouse hepatitis virus (JHMV, a positive-strand RNA virus) results in an acute encephalomyelitis following by a chronic demyelinating disease that shares many similarities with the human demyelinating disease Multiple Sclerosis (MS). Animals develop ascending hind-limb paralysis accompanied by mononuclear cell infiltration into the central nervous system (CNS) and myelin destruction. As such, the JMHV model of demyelination is a well accepted model to study the immunopathological mechanisms contributing to human demyelinating diseases such as MS. T cells and macrophages are considered important contributors to JHMV-induced demyelination as well as demyelination in MS patients. The long-range goal of this proposal is to better understand the molecular mechanisms governing the trafficking and entry of T cells into the CNS following JMHV infection. To this end, studies outlined in this research proposal are designed to evaluate the contributions of the T cell chemoattractant chemokine IP10 (interferon inducible protein 10 kDa) in the pathogenesis of JHMV-induced demyelination. This is padicularly relevant as recent studies have implicated IP-10 as potentially important in contributing to demye!ination in MS patients by attracting T cells into the CNS. in support of this, repots from this laboratory indicate that IP-10 produced by astrocytes contributes to demyelination in JHMV-infected mice by attracting predominantly CD4+ T cells into the CNS of persistently infected mice. Specifically, antibody-mediated neutralization of IP-10 results in reduced neurologic disease, diminished demyelination, and a marked increase in the number of remyellinated axons which correlated with reduced T cell infiltration. Studies outlined in this proposal are designed to increase our understanding of how IP-10 contributes to disease in JHMV-infected mice. Novel strategies designed to accomplish this goal include (i) examination of the molecular mechanisms contributing to IP-10 expression following either viral infection or cytokine treatment of astrocytes and (ii) examining how anti-IP-10 regulates T cell infiltration into the CNS. Together, these studies will extend our current understanding of how IP-10 controls CNS inflammation and demyelination following viral infection.

易感小鼠感染小鼠肝炎病毒（JHMV，一种正链 RNA 病毒）会导致急性脑脊髓炎，随后出现慢性脱髓鞘疾病，与人类脱髓鞘疾病多发性硬化症 (MS) 有许多相似之处。动物出现上行后肢麻痹，并伴有单核细胞浸润中枢神经系统（CNS）和髓鞘质破坏。因此，JMHV 脱髓鞘模型是研究导致人类脱髓鞘疾病（如 MS）的免疫病理学机制的公认模型。 T 细胞和巨噬细胞被认为是 JHMV 诱导的脱髓鞘以及 MS 患者脱髓鞘的重要贡献者。该提案的长期目标是更好地了解 JMHV 感染后控制 T 细胞运输和进入 CNS 的分子机制。为此，本研究提案中概述的研究旨在评估 T 细胞的贡献趋化因子 IP10（干扰素诱导蛋白 10 kDa）在 JHMV 诱导的脱髓鞘发病机制中的作用。这是特别相关的，因为最近的研究表明 IP-10 通过吸引 T 细胞进入中枢神经系统，对 MS 患者脱髓鞘具有潜在的重要作用。为了支持这一点，该实验室的报告表明，星形胶质细胞产生的 IP-10 通过吸引主要 CD4+ T 细胞进入持续感染小鼠的中枢神经系统，从而导致 JHMV 感染小鼠脱髓鞘。具体来说，抗体介导的 IP-10 中和可减少神经系统疾病，减少脱髓鞘，并显着增加髓鞘再生轴突的数量，这与 T 细胞浸润的减少相关。该提案中概述的研究旨在加深我们对 IP-10 如何导致 JHMV 感染小鼠疾病的理解。旨在实现这一目标的新颖策略包括（i）检查病毒感染或星形胶质细胞细胞因子处理后促进 IP-10 表达的分子机制，以及 (ii) 检查抗 IP-10 如何调节 T 细胞浸润到 CNS。总之，这些研究将扩展我们目前对 IP-10 如何控制病毒感染后中枢神经系统炎症和脱髓鞘的理解。