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: 6947370
• 负责人: LAURA A NAPOLITANO
• 金额: $ 28.9万
• 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 2007-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6947370
• 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感染引起的免疫缺陷，通常以T细胞丢失和感染引起的疾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。尽管人们通常认为胸腺只在生命早期才活跃，但越来越多的证据表明，胸腺储备会持续到成年，并在需要的时候被召唤出来。我们之前假设，旨在增强T淋巴生成的疗法可能促进免疫恢复。在一项针对5名HIV-1感染的免疫缺陷成人的前瞻性研究中，我们发现人类生长激素的施用与胸腺退化的逆转和循环初始CD4+ T细胞的增加有关。这些数据提供了有希望的证据，表明在免疫缺陷期间，新生T细胞的产生可能是可诱导的。