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: 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
• 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

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）对免疫系统构成了独特的挑战，因为它被认为是一种免疫学专业的隔室，它位于非延伸屏障后面，并显着限制了抗原呈递机械的表达。由于中枢神经系统是分室的，并在适应性免疫系统上施加了严格的调节机制，因此感染了人类（例如HIV，HIV，疱疹病毒，麻疹病毒，HTLV-1，JC病毒等）的多种病原体能够在CNS中确定持久性。这些持续性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。持续的感染可以通过首先在外围建立持久性来获得访问中枢神经系统的感染。因此，这种常见的情况呈现出生物医学研究人员的挑战，即从外围和中枢神经系统中消除病原体。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，因此我们假设从该专业隔室获得清除率将比外围组织更具挑战性。拟议的研究将探索一种鼠模型系统，在该系统中，通过外围途径引入免疫抑制病毒，然后在中枢神经系统中建立长时间的持久性，尽管最终从外围有清除率。外围的清除与病毒特异性T细胞的功能重新激活相吻合（我们希望在人类中实现的情况），但是这种反应无法阻止中枢神经系统内的病毒持久性。重要的是，在CNS病毒感染峰值处的外源记忆T淋巴细胞的给药可有效清除外周和CNS病毒。因此，尽管内源性免疫反应不足，但经过转移的记忆T淋巴细胞仍可以成功清除。拟议的研究旨在通过建立内源性T细胞反应的缺点（特定的目标＃1）和非常成功的继承反应的作案操作数（特定的目标＃2），从而显着提高了我们对CNS持续病毒感染的T细胞免疫的理解。这项研究的主要目的是从机械上定义了导致CNS病毒清除率成功的因素，以便我们能够更好地补充失败（或不充分的）内源性反应。