Positron Emission Tomography to Evaluate Thymic Function

正电子发射断层扫描评估胸腺功能

• 批准号: 7124644
• 负责人: LAURA A NAPOLITANO
• 金额: $ 23.44万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-20 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7124644
• 关键词: T lymphocyte; bioimaging /biomedical imaging; imaging /visualization /scanning; immune response; immunosenescence; laboratory mouse; leukopoiesis; molecular /cellular imaging; positron emission tomography; somatotropin; technology /technique development; thymus

DESCRIPTION (provided by applicant): Acquired immunodeficiencies, such as those caused by human immunodeficiency virus (HIV)-1 infection, are frequently characterized by T cell loss and an increased risk of illness or death from infection. Since the thymus is the primary site of T cell development, the state of thymic function in an immunodeficient individual may be a pivotal factor in determining the potential for T cell recovery. Although the thymus is generally thought to be active only early in life, accumulating evidence suggests that a thymic reserve persists into adulthood and that it can be summoned in times of need. We have previously hypothesized that therapies designed to enhance T lymphopoiesis might facilitate immune restoration. In a prospective study of 5 immunodeficient adults with HIV-1 infection, we found that the administration of human growth hormone was associated with reversal of thymic involution and an increase in circulating naive CD4+ T cells. These data offer promising evidence that de novo T cell production might be inducible during immunodeficiency. There is growing interest in therapeutic strategies to enhance T cell production in immunodeficient hosts; however the development of such strategies is hindered by a paucity of tools that directly measure thymic function. The uptake of fluorine-18 fluorodeoxyglucose by thymic tissue has been previously detected and quantitated by positron emission tomography (PET). Such uptake is dependent upon the presence of metabolically active cells and therefore may provide a non-invasive measure of thymocyte production within the thymus. The application of PET imaging towards functional assessment of the thymus would represent a novel approach to the quantitation and evaluation of thymic function. The central hypothesis of this proposal is that evaluation of the thymus by PET will provide a direct measurement of thymic function and will reveal functional enhancements induced by therapies designed to stimulate new T cell production. This hypothesis will be examined in mice using microPET technology. Measurement of thymic function by PET will be compared to morphologic, histologic and immunologic assays of thymic function. The following specific aims are proposed: 1) Evaluate PET as a means of directly quantifying thymic function: longitudinal and cross-sectional analyses will be conducted to determine the ability of PET to measure age-associated decreases in thymic function. 2) Apply PET technology towards direct functional assessment of the thymus during the administration of therapy that enhances thymopoiesis: PET will be used to directly quantify changes in thymic function in mice treated with growth hormone, a known enhancer of thymopoiesis. The primary goal of this research is to explore and validate a novel means of assessing thymic function. PET technology may offer a low risk, low complexity procedure that could provide a direct and quantitative measurement of thymic function. If successful, such non-invasive monitoring could represent a very powerful means by which to measure thymic function in the future. Proximate applications of this technology could encompass basic immunologic research as well as pre-clinical and clinical investigations in animals or humans. Such studies might include: measurement of thymic function in the development and evaluation of immune-based therapies and/or vaccinations; investigation of thymic function and aging; investigation of mechanisms regulating T lymphopoiesis; and the development of thymus-specific reagents or reporter genes to further advance functional imaging of the thymus.

描述(由申请人提供)：获得性免疫缺陷，如由人类免疫缺陷病毒(HIV)-1感染引起的，通常以T细胞丢失和感染致病或死亡风险增加为特征。由于胸腺是T细胞发育的主要部位，免疫缺陷个体的胸腺功能状态可能是决定T细胞恢复潜力的关键因素。尽管胸腺通常被认为只有在生命早期才活跃，但越来越多的证据表明，胸腺储备一直持续到成年，在需要的时候可以召唤它。我们之前曾假设，旨在增强T淋巴细胞生成的治疗方法可能有助于免疫恢复。在一项对5名感染HIV-1的免疫缺陷成人进行的前瞻性研究中，我们发现，给予人类生长激素与胸腺退化的逆转和循环中原始CD4+T细胞的增加有关。这些数据提供了有希望的证据，证明在免疫缺陷期间可能会诱导从头产生T细胞。 人们对提高免疫缺陷宿主T细胞生成的治疗策略越来越感兴趣；然而，由于缺乏直接测量胸腺功能的工具，此类策略的发展受到阻碍。胸腺组织对氟-18氟脱氧葡萄糖的摄取已通过正电子发射断层扫描(PET)进行了检测和定量。这种摄取依赖于代谢活跃细胞的存在，因此可以提供胸腺内胸腺细胞产生的非侵入性测量。将PET成像应用于胸腺功能评价，将为胸腺功能的定量和评价提供一种新的方法。 这项建议的中心假设是，PET对胸腺的评估将提供胸腺功能的直接测量，并将揭示旨在刺激新T细胞产生的治疗方法所诱导的功能增强。这一假说将用微型PET技术在小鼠身上进行检验。用PET测量胸腺功能将与胸腺功能的形态学、组织学和免疫学分析进行比较。建议的具体目标如下：1)评价PET作为一种直接量化胸腺功能的手段：将进行纵向和横断面分析，以确定PET测量与年龄相关的胸腺功能下降的能力。2)将PET技术应用于增强胸腺生成的治疗期间对胸腺的直接功能评估：PET将用于直接量化使用生长激素治疗的小鼠胸腺功能的变化，生长激素是一种已知的胸腺生成增强剂。 这项研究的主要目的是探索和验证一种评估胸腺功能的新方法。PET技术可能提供一种低风险、低复杂性的方法，可以提供对胸腺功能的直接和定量测量。如果成功，这种非侵入性监测可能是未来测量胸腺功能的一种非常强大的手段。这项技术的近期应用可能包括基础免疫学研究以及动物或人类的临床前和临床研究。这些研究可能包括：在基于免疫的治疗和/或疫苗的开发和评估中测量胸腺功能；调查胸腺功能和衰老；研究调节T淋巴细胞生成的机制；以及开发胸腺特异性试剂或报告基因，以进一步促进胸腺功能成像。