Effects of Growth Hormone and Insulin-like Growth Factor-1 on Thymopoiesis

生长激素和胰岛素样生长因子1对胸腺生成的影响

• 批准号: 7121698
• 负责人: LAURA A NAPOLITANO
• 金额: $ 28.8万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7121698
• 关键词: growth factor; human; infection; insulin; model; somatotropin; stromal cells; thymus

DESCRIPTION (provided by applicant): Infection with human immunodeficiency virus type 1 (HIV) is characterized by T cell loss and 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, evidence suggests that a thymic reserve persists into adulthood and can be summoned in times of need. We previously hypothesized that therapies designed to enhance T lymphopoiesis might facilitate immune restoration. Based upon data from animal studies suggesting growth hormone (GH) enhances thymic function, we conducted a prospective study of 5 adults with HIV infection, and found that GH therapy was associated with reversal of thymic involution and increased circulating naive CD4+ T cells. These results suggest that T cell production may be inducible during immunodeficiency. Despite its clinical promise, mechanisms of GH action remain unclear. GH seemingly acts by reversing processes that underlie thymic involution, yet these processes are not well established. While some data indicate that proliferative defects in hematopoietic progenitor cells (HPCs) contribute significantly to thymic involution, other data suggest that decreased thymic function is due to an inability of the thymic stromal compartment to support the expansion and maturation of HPCs. It is likely that hematopoietic and thymopoietic deficits coexist and that, combined, they are sufficient to impede normal thymopoiesis. Hence, potential immune targets of GH remain broadly defined. The central hypothesis of this proposal is that thymic stromal cells are a primary target of GH effects on thymopoiesis and that GH enhances stromal expression of factors that facilitate the recruitment, migration, survival, or expansion of newly arrived HPCs. These effects could be induced directly by GH, or by its proximal mediator, insulin-like growth factor-1 (IGF-1). The specific aims of this proposal are to 1) Characterize human thymic stromal populations and investigate their functional responses to in vitro treatment with GH and IGF-1 and 2) Investigate in vivo effects of GH and IGF-1 on human thymopoiesis in the SCID-hu Thy/Liv model. The overall objective of this proposal is to identify GH and IGF-1 targets within the central immune system and provide a comprehensive analysis of changes in the human thymus in response to in vivo administration of GH and IGF-1. If successful, this information would be directly applicable to the future development of targeted therapies to enhance T cell production in immunodeficient individuals.

描述（由申请人提供）：感染人类免疫缺陷病毒1型（HIV）的特征是T细胞丢失和感染引起的疾病或死亡风险增加。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活跃，但有证据表明，胸腺储备会持续到成年，并在需要时被召唤出来。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。基于动物研究数据表明生长激素（GH）可以增强胸腺功能，我们对5名HIV感染的成人进行了一项前瞻性研究，发现GH治疗与胸腺退化的逆转和循环初始CD4+ T细胞的增加有关。这些结果提示免疫缺陷期间T细胞的产生可能是可诱导的。尽管有临床应用前景，生长激素的作用机制仍不清楚。生长激素似乎是通过逆转胸腺退化的过程来起作用的，然而这些过程并没有得到很好的证实。虽然一些数据表明造血祖细胞（HPCs）的增殖缺陷对胸腺退化起着重要作用，但其他数据表明，胸腺功能下降是由于胸腺间质室无法支持HPCs的扩张和成熟。造血功能和胸腺功能的缺陷可能共存，两者结合起来就足以阻碍正常的胸腺功能。因此，生长激素的潜在免疫靶点仍然被广泛定义。该建议的中心假设是胸腺基质细胞是生长激素对胸腺生成作用的主要目标，生长激素增强基质细胞中促进新到达的HPCs募集、迁移、存活或扩增的因子的表达。这些作用可由生长激素直接诱导，或由其近端介质胰岛素样生长因子-1 （IGF-1）诱导。本研究的具体目的是：1)表征人类胸腺基质群体，并研究它们对体外生长激素和IGF-1治疗的功能反应；2)在SCID-hu Thy/Liv模型中研究生长激素和IGF-1对人类胸腺生成的体内影响。本提案的总体目标是确定中枢免疫系统中的生长激素和IGF-1靶点，并提供对体内给药生长激素和IGF-1后人类胸腺变化的全面分析。如果成功，这一信息将直接适用于未来的靶向治疗的发展，以提高免疫缺陷个体的T细胞生产。