HORMONE AND CYTOKINE INFLUENCES ON THYMIC INVOLUTION

胸腺退化是一个渐进的过程， 正常胸腺结构紊乱，同时伴有 胸腺细胞和脂肪替代正常组织。对合减少 胸腺的内分泌功能和这个器官 作为T淋巴细胞分化的主要部位。 已经 一般认为胸腺退化对T细胞的影响 分化是细胞数量的整体减少， 发展道路。 然而，本报告中提供的初步数据显示， 建议主张一个不同的假设，即具体步骤的 胸腺内T细胞分化序列被优先抑制 在退化过程中。数据表明，发展的早期阶段 序列受到对合过程的抑制， 胸腺细胞中CD 4 CD 8 Pgp-1的积累。第一个具体目标是 测试这个假设。实验提出将评估的影响 胸腺退化对各种胸腺细胞亚群相对频率的影响 以及不同表型种群之间的转换率， 代表发育序列中不同的中间体。变化 淋巴区室固有的与 将区分网状上皮隔室。特别侧重 将是细胞因子，特别是IL-7的产生和活性。 本提案的第二个具体目标是检验以下假设： 生长激素和催乳素调节胸腺内T细胞成熟， 因此是对合过程的组成部分。这些脑垂体激素 已被证明是胸腺完整性和外周的重要调节因子 免疫反应。本提案将确定它们在以下方面的作用： 出生后T细胞发育，特别是在Aim-I所示的那些步骤中， 在退化过程中受到影响。 本提案的目标是准确界定： 胸腺内T细胞分化是退化的结果 以及生长激素和催乳素参与维持 正常的胸腺生成

Thymic involution is a gradual progressive process resulting in the disorganization of normal thymic architecture, coincident with a loss of thymocytes, and replacement of normal tissue with fat. Involution reduces both the endocrine function of the thymus and the ability of this organ to serve as the major site of T lymphocyte differentiation. It has been generally assumed that the effect of thymic involution on T cell differentiation is a global reduction in the number of cells moving through the developmental pathway. However, preliminary data presented in this proposal argues for a different hypothesis, that specific steps of the intrathymic T cell differentiation sequence are preferentially inhibited during involution. The data suggest that early steps in the developmental sequence are inhibited by the involution process resulting in an accumulation of CD4CD8 Pgp-1hi thymocytes. The first specific aim, is to test this hypothesis. Experiments are proposed which will assess the impact of thymic involution on the relative frequency of various thymocyte subsets and the rate of transition between different phenotypic populations which represent distinct intermediates in the developmental sequence. Changes intrinsic to the lymphoid compartment versus those intrinsic to the reticuloepithelial compartment will be distinguished. A particular focus will be the production and activity of cytokines, especially IL-7. The second specific aim of this proposal is to test the hypothesis that growth hormone and prolactin regulate intrathymic T cell maturation and thus are integral to the involution process. These pituitary hormones have been shown to be important regulators of thymic integrity and peripheral immune responses. The present proposal will establish their role(s) in postnatal T cell development, particularly in those steps shown in Aim -I to be affected during involution. The objectives of this proposal are to precisely define: the changes in intrathymic T cell differentiation occurring as a consequence of involution and the involvement of growth hormone and prolactin in the maintenance of normal thymopoiesis.