Homeostasis of T cells in primates

灵长类动物 T 细胞的稳态

• 批准号: 6804620
• 负责人: DAVID A GARBER
• 金额: $ 31.32万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-30 至 2007-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6804620
• 关键词: Cercocebus; Macaca mulatta; T lymphocyte; bone marrow; cell population study; cellular immunity; cytokine; developmental immunology; lymph nodes; lymphocyte proliferation; simian AIDSs; species difference; thymectomy

DESCRIPTION (provided by applicant): Little is known about the mechanisms regulating T cell homeostasis in primates. The overall aim of this project is to study the homeostatic regulation of T cells in healthy rhesus macaques (RM) and sooty mangabeys (SM) via antibody-induced depletion of specific T cell subsets. We believe that this proposal is relevant to AIDS research due to the specific features of SIV-infection in the two species, i.e. pathogenic in RM and non-pathogenic in SM. If our study identifies differences in T cell homeostasis between RM and SM, we may then hypothesize that these differences play a role in determining the clinical outcome after SIV-infection. In earlier studies we showed that although CD4+ T cells are lost due to the cytopathic effect of the virus during both pathogenic and non-pathogenic infections, only in pathogenic infections is the homeostasis of T cells lost. This observation suggests that the failure of T cell homeostasis may play a role in the pathogenesis of AIDS, and that treatments aimed at reconstituting this homeostasis may be used in the clinical management of HIV-infected patients. Here we propose to study the lymphocyte repopulation that follows CD4+ and CD8+ T cell depletion by sequentially sampling bone marrow (BM), peripheral blood (PB) and lymph nodes (LN). The performed analyses will include: (1) immunophenotypic studies, (2) determination of levels of recent thymic emigrants, and (3) examination of levels of cytokines, i.e. IL-7, IL-15and IL-2, that may play a role in T cell homeostasis. In this application we also propose to evaluate the role of the thymus in T cell homeostasis by performing CD4+ and CD8+ T cell depletions in both normal and thymectomized animals. We believe that this comparative study may provide information on (1) the differential role of BM, LN and thymus in T cell homeostasis; (2) the specific features of the homeostasis ofCD4+ and CD8+ T cells; (3) the immunophenotype of T cells that are proliferating via homeostatic mechanisms; and (4) the role of cytokines in reconstituting acutely depleted T cell populations. Importantly, this approach may allow us to define differences in the way T cell homeostasis is maintained in RM vs SM, which could provide clue regarding the markedly different impact of SIV-infection in the two species. In all, we believe that this project may provide useful information on the homeostasis of T cells in primates, and how the failure of this homeostasis may play a role in the pathogenesis of AIDS.

描述（由申请人提供）：对于灵长类动物 T 细胞稳态的调节机制知之甚少。该项目的总体目标是通过抗体诱导特定 T 细胞亚群的耗竭，研究健康恒河猴 (RM) 和乌白眉猴 (SM) 中 T 细胞的稳态调节。我们认为，由于两个物种中 SIV 感染的具体特征，即 RM 为致病性，SM 为非致病性，因此该提案与 AIDS 研究相关。如果我们的研究确定了 RM 和 SM 之间 T 细胞稳态的差异，那么我们可以假设这些差异在确定 SIV 感染后的临床结果中发挥着作用。在早期的研究中，我们表明，尽管在致病性和非致病性感染期间，CD4+ T 细胞由于病毒的细胞病变作用而丢失，但只有在致病性感染中，T 细胞的稳态才会丢失。这一观察结果表明，T 细胞稳态的失败可能在 AIDS 的发病机制中发挥作用，旨在重建这种稳态的治疗可用于 HIV 感染患者的临床管理。在这里，我们建议通过连续采样骨髓（BM）、外周血（PB）和淋巴结（LN）来研究 CD4+ 和 CD8+ T 细胞耗竭后的淋巴细胞重新增殖。进行的分析将包括：(1) 免疫表型研究，(2) 测定近期胸腺移出物的水平，以及 (3) 检查可能在 T 细胞稳态中发挥作用的细胞因子水平，即 IL-7、IL-15 和 IL-2。在此应用中，我们还建议通过在正常和胸腺切除动物中进行 CD4+ 和 CD8+ T 细胞耗竭来评估胸腺在 T 细胞稳态中的作用。我们认为，这项比较研究可能提供以下信息：(1) BM、LN 和胸腺在 T 细胞稳态中的不同作用； (2)CD4+和CD8+T细胞稳态的具体特征； (3) 通过稳态机制增殖的 T 细胞的免疫表型； (4) 细胞因子在重建严重耗尽的 T 细胞群中的作用。重要的是，这种方法可以让我们定义 RM 与 SM 中 T 细胞稳态维持方式的差异，这可以提供有关 SIV 感染对这两个物种的显着不同影响的线索。总之，我们相信这个项目可以提供有关灵长类动物 T 细胞稳态的有用信息，以及这种稳态的失败如何在艾滋病的发病机制中发挥作用。