In Vivo Analysis of T lymphocytes in the Persistently Infected CNS

持续感染中枢神经系统中 T 淋巴细胞的体内分析

基本信息

批准号：
7570017
负责人：
MICHAEL B OLDSTONE
金额：
$ 46.47万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-03-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7570017
关键词：
Address Adenoviruses Adoptive Immunotherapy Affect Antigens Astrocytes Behavioral Biological Models Brain Central Nervous System Viral Diseases Cessation of life Chronic Phase Cytopathology Effectiveness Environment Epitopes Failure HIV Health Herpesviridae Human Human T-lymphotropic virus 1 Immune Immune response Immune system Immunity Immunosuppressive Agents Infection JC Virus Lymphocytic choriomeningitis virus Major Histocompatibility Complex Measles virus Modeling Modus Mus Neuraxis Neurologic Dysfunctions Neurons Peripheral Phase Population Price Property Recovery of Function Recruitment Activity Regulation Research Research Personnel Route Source T memory cell T-Lymphocyte Time Tissues Toxic effect Tropism Viral Virus Virus Diseases cytokine design exhaustion immunopathology in vivo insight neurobehavioral neurotropic virus novel olfactory bulb pathogen pressure prevent programs purge response stem

项目摘要

DESCRIPTION (provided by applicant): The central nervous system (CMS) poses a unique challenge to the immune system, as it is considered an immunologically specialized compartment that resides behind a non-fenestrated barrier and significantly limits the expression of antigen-presenting machinery. Because the CNS is compartmentalized and imposes strict regulatory mechanisms on the adaptive immune system, a multitude of pathogens that infect humans (e.g. HIV, herpes virus, measles virus, HTLV-1, JC virus, etc.) are capable of establishing persistence in the CNS. These persistent infections can give rise to severe behavioral alterations and neurological dysfunction, which adversely affects human health. Persistent infections that gain access to the CNS often do so by first establishing persistence in the periphery. This common scenario consequently presents biomedical researchers with the challenge of eradicating the pathogen from both the periphery as well as the CNS. Given that the CNS provides such a favorable environment to viruses seeking persistence, we postulate that achieving clearance from this specialized compartment will be far more challenging than from peripheral tissues. The proposed study will explore a murine model system in which an immunosuppressive virus is introduced through a peripheral route and then establishes prolonged persistence in the CNS despite the eventual clearance from the periphery. Clearance from the periphery coincides with a functional reactivation of virus-specific T cells (a scenario we hope to achieve in humans), yet this response is unable to prevent prolonged viral persistence within the CNS. Importantly, administration of exogenous memory T lymphocytes at the peak of CNS viral infection results in efficient clearance of the virus from both the periphery and the CNS. Thus, an adoptively transferred population of memory T lymphocytes can achieve successful clearance despite an inadequate endogenous immune response. The proposed study is designed to significantly advance our understanding of T cell immunity to persistent viral infections in the CNS by establishing the shortcomings of the endogenous T cell response (Specific Aim#1) and the modus operand of a highly successful adoptive response (Specific Aim#2). The main objective of this research is mechanistically define the factors that give rise to successful CNS viral clearance so that we are better able to supplement a failing (or inadequate) endogenous response.

描述（由申请人提供）：中枢神经系统（CMS）对免疫系统提出了独特的挑战，因为它被认为是一个免疫学专用区室，位于无窗屏障后面，并显着限制了抗原呈递机制的表达。由于中枢神经系统是分开的，并对适应性免疫系统施加严格的调节机制，因此感染人类的多种病原体（例如 HIV、疱疹病毒、麻疹病毒、HTLV-1、JC 病毒等）能够在体内建立持久性。中枢神经系统。这些持续感染会导致严重的行为改变和神经功能障碍，从而对人类健康产生不利影响。进入中枢神经系统的持续感染通常首先在外围建立持久性。因此，这种常见情况给生物医学研究人员带来了从外周和中枢神经系统根除病原体的挑战。鉴于中枢神经系统为寻求持久性的病毒提供了如此有利的环境，我们假设从这个特殊的隔间中实现清除将比从外周组织中实现清除更具挑战性。拟议的研究将探索一种小鼠模型系统，其中免疫抑制病毒通过外周途径引入，然后在中枢神经系统中建立长期持续存在，尽管最终从外周清除。从外周清除的同时，病毒特异性 T 细胞的功能重新激活（我们希望在人类中实现的情况），但这种反应无法阻止病毒在中枢神经系统内长期存在。重要的是，在 CNS 病毒感染高峰期施用外源记忆 T 淋巴细胞可以有效清除外周和 CNS 中的病毒。因此，尽管内源性免疫反应不足，但过继转移的记忆T淋巴细胞群仍能成功清除。拟议的研究旨在通过确定内源性 T 细胞反应的缺点（具体目标#1）和高度成功的过继反应的操作方式（具体目标），显着增进我们对中枢神经系统中持续性病毒感染的 T 细胞免疫的理解。＃2）。这项研究的主要目标是从机械上定义导致中枢神经系统病毒成功清除的因素，以便我们能够更好地补充失败（或不足）的内源性反应。