Growth Hormone/Insulin-Like Growth Factor-1/T-Cell

生长激素/胰岛素样生长因子-1/T 细胞

• 批准号: 6843913
• 负责人: LAURA A NAPOLITANO
• 金额: $ 26.85万
• 依托单位: J. DAVID GLADSTONE INSTITUTES
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2006-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6843913
• 关键词: AIDS therapy; T lymphocyte; clinical research; cytomegalovirus; flow cytometry; human subject; immune response; insulinlike growth factor; leukocyte count; monocyte; patient oriented research; somatotropin; tissue /cell culture

DESCRIPTION (provided by applicant): Recent progress in antiretroviral therapy makes the immunosuppression of human immunodeficiency virus, type 1 (HIV) disease partially reversible, however the degree of immune recovery is more complete in some individuals than in others. Despite effective suppression of HIV replication with highly active antiretroviral therapy (HAART), CD4+ T cells do not increase in some HAART-treated individuals. Even in the setting of quantitative CD4+ T cell recovery, HAART recipients retain qualitative abnormalities in immune function that include impairments in peripheral T cell proliferation and maturation, and marked deficits in HIV-specific immunity. The long-term goal of this research is to explore and develop immune-based strategies that will enhance T cell production and function in immunodeficient individuals. Growth hormone (GH) and its proximal mediator, insulin-like growth factor (IGF-1), are important regulators of T cell development and function in mammals. GH and IGF-1 reverse age-related declines in thymopoiesis in older rodents and accelerate immune reconstitution in immunodeficient animals. Recently these findings were extended to human studies, which demonstrated that GH treatment of HIV-infected adults was associated with a dramatic increase in thymic mass and an increase in circulating naive CD4+ T cells. Accumulating evidence from in vitro and in vivo studies suggest that GH and IGF-1 may also regulate and potentiate peripheral immune function. The central hypothesis of this proposal is that growth hormone will enhance antigen-specific T cell responses in HIV infected adults. Augmentation of peripheral immune responses may be mediated by GH induction of de novo T cell production by the thymus, or by its effects on targets within the peripheral immune system. The specific aims of our research are to: 1. Investigate the effects of GH and IGF-1 on human T cell function in vitro. We will conduct analyses to examine how GH and IGF-1 modulate the survival, proliferation, activation, cytokine production and cytotoxicity of peripheral T cells, including specific analysis of na'ive and memory/effector subsets. 2. Determine whether growth hormone treatment enhances antigen-specific immune responses in HIV-infected adults. We will perform longitudinal analysis of HIV and CMV-specific immune responses in the context of a randomized prospective clinical study examining the effects of GH on the immune system of HIV-infected adults.

描述（由申请人提供）：抗逆转录病毒治疗的最新进展使得人类免疫缺陷病毒 1 型 (HIV) 疾病的免疫抑制部分可逆，但某些个体的免疫恢复程度比其他个体更完全。尽管高效抗逆转录病毒疗法 (HAART) 可有效抑制 HIV 复制，但一些接受 HAART 治疗的个体中 CD4+ T 细胞并未增加。即使在定量 CD4+ T 细胞恢复的情况下，HAART 接受者仍保留免疫功能的质量异常，包括外周 T 细胞增殖和成熟受损，以及 HIV 特异性免疫的明显缺陷。这项研究的长期目标是探索和开发基于免疫的策略，以增强免疫缺陷个体的 T 细胞生成和功能。生长激素 (GH) 及其近端介质胰岛素样生长因子 (IGF-1) 是哺乳动物 T 细胞发育和功能的重要调节因子。 GH 和 IGF-1 可以逆转老年啮齿动物中与年龄相关的胸腺生成能力下降，并加速免疫缺陷动物的免疫重建。最近，这些发现扩展到人体研究，证明对 HIV 感染的成年人进行 GH 治疗与胸腺质量的急剧增加和循环初始 CD4+ T 细胞的增加有关。越来越多的体外和体内研究证据表明，GH 和 IGF-1 还可以调节和增强外周免疫功能。该提案的中心假设是生长激素将增强 HIV 感染成人的抗原特异性 T 细胞反应。外周免疫反应的增强可能是通过 GH 诱导胸腺从头产生 T 细胞来介导的，或者是通过其对外周免疫系统内靶标的影响来介导的。我们研究的具体目标是： 1. 体外研究GH和IGF-1对人T细胞功能的影响。我们将进行分析，以检查 GH 和 IGF-1 如何调节外周 T 细胞的存活、增殖、激活、细胞因子产生和细胞毒性，包括对初始和记忆/效应子亚群的具体分析。 2. 确定生长激素治疗是否增强 HIV 感染成人的抗原特异性免疫反应。我们将在一项随机前瞻性临床研究的背景下对 HIV 和 CMV 特异性免疫反应进行纵向分析，该研究检查 GH 对 HIV 感染成人的免疫系统的影响。