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

• 批准号: 8026029
• 负责人: MICHAEL B OLDSTONE
• 金额: $ 45.55万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8026029
• 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 cell response; 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

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）对免疫系统构成独特的挑战，因为它被认为是一种免疫学特化区室，位于无窗屏障后面，并显著限制抗原呈递机制的表达。因为CNS是区室化的并且对适应性免疫系统施加严格的调节机制，所以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）可以通过免疫系统或免疫系统来调节。能够在CNS中建立持久性。这些持续感染可引起严重的行为改变和神经功能障碍，对人类健康产生不利影响。持续性感染进入中枢神经系统通常首先在外周建立持续性。这种常见的情况，因此提出了生物医学研究人员的挑战，根除病原体从外周以及中枢神经系统。鉴于中枢神经系统为寻求持久存在的病毒提供了如此有利的环境，我们假设从这个专门的区室中清除病毒将比从外周组织中清除病毒更具挑战性。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CNS中建立长期持久性，尽管最终从外周清除。从外周的清除与病毒特异性T细胞的功能性再活化相一致（我们希望在人类中实现的情况），但这种反应无法阻止CNS内病毒的长期持续存在。重要的是，在CNS病毒感染高峰时施用外源性记忆T淋巴细胞导致病毒从外周和CNS两者的有效清除。因此，过继转移的记忆T淋巴细胞群体可以实现成功的清除，尽管内源性免疫应答不足。拟定的研究旨在通过确定内源性T细胞应答（特异性目标#1）的缺点和高度成功的过继性应答（特异性目标#2）的操作方式，显著提高我们对CNS中持续性病毒感染的T细胞免疫力的理解。本研究的主要目的是从机制上确定导致成功清除CNS病毒的因素，以便我们能够更好地补充失败（或不足）的内源性应答。