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.
