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）对免疫系统提出了独特的挑战，因为它被认为是一个免疫特异性的隔室，位于无孔屏障后面，显著限制了抗原呈递机制的表达。由于中枢神经系统是区隔的，并对适应性免疫系统施加严格的调节机制，许多感染人类的病原体（如HIV、疱疹病毒、麻疹病毒、HTLV-1、JC病毒等）能够在中枢神经系统中建立持久性。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。进入中枢神经系统的持续性感染通常首先在外周建立持久性。因此，这种常见的情况向生物医学研究人员提出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，我们假设从这个专门的隔室获得清除将比从外周组织获得清除要困难得多。该研究将探索一个小鼠模型系统，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持久的持久性，尽管最终从外周清除。来自外周的清除与病毒特异性T细胞的功能性再激活相一致（我们希望在人类中实现这种情况），然而这种反应无法阻止病毒在中枢神经系统内的长时间持续存在。重要的是，在中枢神经系统病毒感染的高峰期，外源性记忆T淋巴细胞的管理导致病毒从外周和中枢神经系统的有效清除。因此，尽管内源性免疫反应不足，但过继性转移的记忆T淋巴细胞群体可以成功清除。本研究旨在通过确定内源性T细胞应答的缺陷（Specific Aim#1）和高度成功的过继应答的操作方式（Specific Aim#2），显著提高我们对中枢神经系统持续病毒感染的T细胞免疫的理解。本研究的主要目的是从机制上确定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（或不充分）的内源性反应。