Chemokine IP-10 and Viral-Induced Demyelination

趋化因子 IP-10 和病毒引起的脱髓鞘

• 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
• 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

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.

用小鼠肝炎病毒（JHMV，一种正链RNA病毒）感染易感小鼠导致急性脑脊髓炎，随后发生慢性脱髓鞘疾病，其与人类脱髓鞘疾病多发性硬化症（MS）有许多相似之处。动物发生上行性后肢麻痹，伴有单核细胞浸润到中枢神经系统（CNS）和髓鞘破坏。 因此，脱髓鞘的JMHV模型是研究有助于人类脱髓鞘疾病如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患者中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T细胞进入CNS的分子机制。 为此，本研究计划中概述的研究旨在评估T细胞的贡献。 趋化因子IP 10（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padicularly相关的，因为最近的研究表明，IP-10作为潜在的重要贡献demye！通过将T细胞吸引到CNS中来在MS患者中进行诱导。支持这一点的是，来自该实验室的报告表明，星形胶质细胞产生的IP-10通过主要吸引CD 4 + T细胞进入持续感染小鼠的CNS而导致JHMV感染小鼠的脱髓鞘。 具体而言，抗体介导的IP-10中和导致神经疾病减少、脱髓鞘减少和与T细胞浸润减少相关的髓鞘再生轴突数量显著增加。本提案中概述的研究旨在增加我们对IP-10如何导致JHMV感染小鼠疾病的理解。为实现这一目标而设计的新战略包括：（i） 检查在病毒感染或细胞因子处理星形胶质细胞后有助于IP-10表达的分子机制，和（ii）检查抗IP-10如何调节T细胞浸润到CNS中。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CNS炎症和脱髓鞘的理解。