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T CELL RESPONSES DURING ACUTE VIRAL ENCEPHALITIS

急性病毒性脑炎期间 T 细胞的反应

基本信息

批准号：
2445647
负责人：
DAVID N IRANI
金额：
$ 8.07万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1993
资助国家：
美国
起止时间：
1993-09-30 至 1998-12-31
项目状态：
已结题

项目摘要

The inflammatory response to acute Sindbis virus (SV) infection of the central nervous system (CNS) has been characterized in a murine model. This disease is representative of arboviral encephalitis, and it serves as a model to study immune reactions within the CNS. Cerebrospinal fluid inflammation during SV encephalitis, which reaches a peak early in infection, is composed of T cells and natural killer cells. Parenchymal inflammation is maximal later, and appears more complex in cellular composition. The virus is subsequently cleared from the CNS, and mice with the wild-type infection recover uneventfully. The primary goal of the proposed experiments is to characterize the development of the CNS T cell response during SV encephalitis over the full course of the infection. Specific investigations will focus on detailed phenotypic study of T cells that infiltrate the CNS, as well as characterization of their functional properties. These include cytokine production as well as anti-viral proliferative and cytotoxic responsiveness. Other experiments will investigate the significance of preliminary findings which have shown that gamma delta plus T cells accumulate preferentially within the CNS, especially early in infection. Since the specific molecular interactions between T cells and cerebral capillary endothelial cells likely regulate lymphocyte extravasation into the CNS and the development of perivascular inflammation, further goals of this proposal will be to explore the nature of adhesion events between these two cell populations during acute encephalitis. This will be performed using both an in vitro cell adhesion assay between lymphocytes and tissue sections of brain parenchyma from infected animals, as well as with an in vivo assay of T cell homing into the CNS. Blocking experiments with monoclonal antibodies are planned in order to determine the relevant molecular interactions between T cells and CNS microvascular endothelium both in vitro and in vivo. The in vitro assay may also serve to screen for and identify presently uncharacterized receptor-ligand interactions that mediate binding in this setting. Exploring these features of T cells will be important for understanding not only the pathogenesis of acute viral encephalitis, but also other inflammatory conditions of the CNS which are presumed to be T cell-mediated.

儿童对辛德比斯病毒(SV)感染的炎症反应中枢神经系统(CNS)已在小鼠模型中表现出特征。这种疾病是虫媒病毒性脑炎的代表，它的服务作为研究中枢神经系统内免疫反应的模型。脑脊液病毒性脑炎期间的炎症，在早期达到高峰感染，由T细胞和自然杀伤细胞组成。实质炎症后期最严重，在细胞内表现得更为复杂组成。病毒随后从中枢神经系统中清除，小鼠随着野生型感染的顺利康复。的主要目标是拟议的实验是为了刻画中枢神经系统的发育病毒性脑炎全程中的T细胞反应感染。具体调查将侧重于详细的表型 T细胞对中枢神经系统的侵袭及其特性的研究它们的功能特性。这也包括细胞因子的产生。作为抗病毒、增殖和细胞毒性反应。其他实验将调查初步发现的意义这表明伽马增量加T细胞优先蓄积在中枢神经系统内，特别是在感染早期。由于特定的 T细胞与脑毛细血管内皮细胞的分子相互作用细胞可能调节淋巴细胞外溢进入中枢神经系统血管周围炎症的发展，本提案的进一步目标将探索这两个细胞之间黏附事件的本质急性脑炎期间的人群。这将使用两种方式执行淋巴细胞与组织切片的体外细胞黏附实验来自受感染动物的脑实质，以及体内的 T细胞归巢到中枢神经系统的检测。用单抗进行阻断实验计划抗体是为了确定相关的分子 T细胞与中枢神经系统微血管内皮细胞的相互作用体外和体内。体外试验也可用于筛选和确定目前尚未表征的受体-配体相互作用在此设置中中介绑定。探索T细胞的这些特征将会不仅对了解急性病毒的发病机制很重要脑炎，但也有中枢神经系统的其他炎症性状况推测是由T细胞介导的。