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。产生广泛反应的T细胞和维持不同的外周T细胞谱系是人类免疫系统成功的关键。不幸的是，胸腺的生成会因正常衰老而减弱。随着个体年龄的增长，胸腺以未知的机制退化，新T细胞的产量显著下降。随着年龄的增长，失去广泛反应的幼稚外周T细胞会导致成年人对感染和疫苗的免疫反应受到抑制。此外，当成人外周T细胞库因病毒感染(HIV)、化疗或辐射而受损时，有必要用新的T细胞从治疗上重建外周。老年人胸腺的功能状态决定着T细胞重建和免疫的数量和质量。胸腺退缩是一个诱导胸腺细胞凋亡的有序过程。最近的研究表明，IL-6基因家族细胞因子在人和小鼠的胸腺组织中升高，并能有效地抑制小鼠的胸腺生成。这些观察结果导致了一种假说，即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。这项提案的总体目标是定义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翻译给人类，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细胞因子通过定义导致胸腺细胞在整个衰老过程中耗尽的细胞因子和类固醇产生途径来诱导胸腺退化的机制，确定抑制白血病抑制因子和其他胸腺抑制细胞因子是否可以防止或逆转小鼠衰老的胸腺萎缩，以及确定老年小鼠胸腺功能的改善是否可以增强对感染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.