Mechanisms of Age Induced Thymic Atrophy

描述（申请人提供）：胸腺是一个复杂的器官，负责外周T细胞的成熟和教育。产生广泛反应性T细胞和维持多样化的外周T细胞库对人类免疫系统的成功至关重要。不幸的是，胸腺功能随着正常的衰老而减弱。随着个体年龄的增长，胸腺因未知的机制而衰竭，新T细胞的输出显著下降。随着年龄的增长，广泛反应性的初始外周T细胞库的丧失导致成人对感染和疫苗的免疫反应受到抑制。此外，当成人外周T细胞池因病毒感染（HIV）、化疗或照射而受损时，需要用新的T细胞进行治疗性重建外周细胞。老年胸腺的功能状态决定了T细胞重建和免疫的数量和质量。胸腺内化是诱导胸腺细胞凋亡的有序过程。最近有研究表明，IL-6基因家族细胞因子在老年人和小鼠胸腺组织中升高，并积极抑制小鼠胸腺生成。这些观察结果导致假设年龄诱导的胸腺退化是一个由胸腺抑制细胞因子介导的活跃过程。该提案的总体目标是确定参与胸腺组织衰老的关键因素和途径，并准备将新定义的治疗策略转化为人类，以提高成人在各种临床环境中的免疫力。为了实现这一目标，我们提出的具体目标是确定白血病抑制因子和其他胸腺抑制因子通过定义导致胸腺细胞在衰老过程中耗竭的细胞因子和类固醇产生途径诱导胸腺退化的机制，以确定抑制白血病抑制因子和其他胸腺抑制因子是否可以预防或逆转小鼠衰老时的胸腺萎缩。并确定老年小鼠胸腺功能的改善是否可以增强对感染性病原体或疫苗的外周免疫反应。

DESCRIPTION (provided by applicant): The thymus is a complex organ responsible for the maturation and education of peripheral T cells. Production of broadly reactive T cells and maintenance of a diverse peripheral T cell repertoire are critical to the success of the human immune system. Unfortunately, thymopoiesis is attenuated by normal aging. As an individual ages, the thymus involutes by unknown mechanisms and output of new T cells significantly falls. Loss of a broadly reactive naive peripheral T cell repertoire with age results in suppressed immune responses to infections and vaccines in adults. Moreover, when the adult peripheral T cell pool is damaged by viral infection (HIV), chemotherapy, or irradiation, there is a need to therapeutically reconstitute the periphery with new T cells. The functional status of the aged thymus dictates quantity and quality of T cell reconstitution and immunity. Thymic involution is an ordered process resulting in induction of thymocyte apoptosis. It has recently been demonstrated that IL-6 gene family cytokines are elevated in aged human and mouse thymus tissue, and that they actively suppress thymopoiesis in mice. These observations have lead to the hypothesis that age-induced thymic involution is an active process mediated by thymosuppressive cytokines. The overall goal of this proposal is to define critical factors and pathways involved in thymus tissue aging, and be poised to translate newly-defined therapeutic strategies to humans for improved immunity in a variety of clinical settings in adults. The proposed specific aims to accomplish this goal are to determine the mechanisms by which Leukemia Inhibitory Factor and other thymosuppressive cytokines induce thymus involution by defining cytokine and steroid production pathways that result in thymocyte depletion throughout aging, to determine if inhibition of Leukemia Inhibitory Factor and other thymosuppressive cytokines can prevent or reverse thymic atrophy of aging in mice, and to determine if improved thymic function in aged mice can enhance peripheral immune responses to infectious pathogens or vaccines.