Evaluation of thymus function in lentivirus disease

慢病毒病中胸腺功能的评价

• 批准号: 7006335
• 负责人: LAWRENCE E MATHES
• 金额: $ 30.72万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-05 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7006335
• 关键词: Retroviridae disease; T lymphocyte; cats; cell differentiation; cell population study; cellular immunity; cytotoxic T lymphocyte; disease /disorder model; feline immunodeficiency virus; helper T lymphocyte; homeostasis; immunologic memory; leukopoietic factor; lymphadenectomy; suppressor T lymphocyte; thymectomy; thymus; thymus disorder; tissue /cell culture; virus antigen

The timing and mechanisms that underlie the development of thymic dysfunction during HIV infection are largely unknown and difficult to study in humans. Feline immunodeficiency virus (FIV) infection of cats leads to significant pathological changes in the thymus with many similar effects on immune function as seen in HIV-1 infections. We have extensive experience using the FIV/cat model to document thymic pathogenesis and to map temporal changes in thymus integrity and function following FIV infection. Among the these changes is the surprising observation that thymectomy (ThX) of adult cats subsequently infected with FIV led to a rapid loss of virus-specific cytolytic T cell function. The cause of this loss is unknown and may result from a lack of replenishment, CD4+ T-cell functional deficiency, loss of cytokine/thymic hormonal support, failure of CD8+ T-cell maturation, or suppression by T regulatory (T-reg) cells. The overall objective of the proposed studies is to identify the mechanism causing the loss of CTL function and to understand better the broad implications of lentivirus-mediated thymic involution leading to irreversible loss of thymic function. Based on our current understanding of the role of the thymus in maintaining a robust antivirus T-cell response, we offer the overall hypothesis that in adults, sustained cytolytic T-cell responses to HIV-1 require a functional thymus that influences the peripheral T-cell compartment through direct resupply HIV-1 specific T-cell clones, or indirectly through endocrine-like thymic hormones that promote T-cell maturation and effector cell function. We also hypothesize that thymic influence is necessary at the time of initial antigen exposure to augment the immune response either by supplying a burst of naive T-cells or indirectly through endocrine-like thymic hormone that enhance the primary immune response. To test these hypotheses, we propose three Specific Aims. Aim #1 will identify the mechanism(s) that causing the loss of cytolytic CD8+ function in thymectomized, FIV-infected cats. Aim #2 will evaluate the effect of post-infection ThX on maintenance of immune competency. Aim #3 will evaluate the role of the thymus in maintaining recall antigen responses where antigen is given chronically or intermittantly. Using this novel FIV/ThX model, we can monitor immune function in the dynamic context of active lentivirus infection also explore the underlying mechanism by which the thymus participates in maintaining peripheral T-cell homeostasis.

艾滋病毒感染期间胸腺功能障碍发生的时间和机制在很大程度上是未知的，也很难在人类身上进行研究。猫感染猫免疫缺陷病毒(FIV)会导致胸腺发生明显的病理变化，对免疫功能的影响与HIV-1感染相似。我们有丰富的经验使用FIV/CAT模型来记录胸腺的发病机制，并绘制FIV感染后胸腺完整性和功能的时间变化图。在这些变化中，令人惊讶的是观察到，成年猫胸腺切除(THX)随后感染FIV导致病毒特异性细胞溶解T细胞功能迅速丧失。造成这一损失的原因尚不清楚，可能会导致 由于缺乏补充，CD4+T细胞功能缺陷，失去细胞因子/胸腺激素支持，CD8+T细胞成熟失败，或T调节(T-reg)细胞的抑制。这些研究的总体目标是确定导致CTL功能丧失的机制，并更好地了解慢病毒介导的胸腺退缩导致胸腺功能不可逆转丧失的广泛意义。基于我们目前对胸腺在维持强大的抗病毒T细胞反应中的作用的了解，我们提出了总体假设，即在成人中，持续的细胞溶解T细胞对HIV-1的反应需要一个功能正常的胸腺，通过直接再补充HIV-1特异性T细胞克隆或间接通过促进T细胞成熟和效应细胞功能的内分泌样胸腺激素来影响外周T细胞间隔。我们还假设，在初始抗原暴露时，胸腺的影响是必要的，可以通过提供大量幼稚T细胞来增强免疫反应，也可以间接地通过内分泌样胸腺激素来增强初级免疫反应。为了检验这些假设，我们提出了三个具体目标。目的#1将确定导致胸腺切除后感染FIV的猫CD8+细胞溶解功能丧失的机制(S)。目的#2评价感染后THX对维持免疫功能的影响。目的#3将评估胸腺在慢性或间歇性给予抗原时维持回忆性抗原反应中的作用。使用这种新的FIV/THX模型，我们可以监测活跃慢病毒感染的动态背景下的免疫功能，并探索胸腺参与维持外周T细胞稳态的潜在机制。