T regulatory cells in Rhesus Macaques and African green monkeys

恒河猴和非洲绿猴的 T 调节细胞

• 批准号: 7244050
• 负责人: Ivona Vasile Pandrea
• 金额: $ 20.03万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-06-01 至 2008-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7244050
• 关键词: Acquired Immunodeficiency Syndrome; African; Alveolar; Biological Preservation; Blood Cells; Cell Count; Cells; Cercocebus atys; Cercopithecus pygerythrus; Chronic; Collaborations; Data; Flow Cytometry; Future; HIV; Hour; Human; IL2RA gene; Immune; Immune System Diseases; In Vitro; Infection; Interleukin 2 Receptor; Intestines; Irrigation; Knowledge; Lung; Lymphocyte Activation; Macaca; Macaca mulatta; Mandrillus sphinx; Modeling; Monkeys; Mus; Neuropilin-1; Normal tissue morphology; Numbers; Pathogenesis; Pattern; Pharmaceutical Preparations; Play; Role; SIV; Staging; Study models; T-Cell Activation; T-Lymphocyte; T-Lymphocyte Subsets; Tissues; Universities; Viral; density; design; experience; in vivo; lymph nodes; nonhuman primate; research study

DESCRIPTION (provided by applicant): The objective of this project is to examine T regulatory cells (Tregs) in Rhesus macaques (Rh) and African green monkeys (AGMs). Tregs, initially defined as CD4+CD25+, suppress T-cell activation and proliferation in mice and humans. As chronic immune activation and rapid turnover of T cells are hallmarks of pathogenic HIV/SIVmac infections in humans and Rh, these cells may play an important role in HIV/SIV pathogenesis. Rh and AGMs, the best models for the study of SIV pathogenesis, differ in one fundamental aspect: Rh infected SIVmac develop AIDS, while AGMs infected with SIVagm typically remain healthy. Our preliminary studies showed a loss of CD4+CD25+ T cells in SIVmac-infected Rh that may explain the aberrant chronic T cell hyperactivation described in this pathogenic infection. In contrast, we have found an increase in the number of Tregs during very early stages of SIVagm infection and a better preservation of CD4+CD25+ T cells in chronically SIVagm-infected AGMs. The pattern of CD4+CD25+ T cell dynamics in SIVagm-infected AGMs corroborates the lack of immune activation and turnover during SIV infection in natural hosts. We therefore hypothesize that fully functional Tregs are present in non-human primates and may play a protective role in SIV infection. To clearly define the role of Tregs in pathogenic and non- pathogenic SIV infections, we designed experiments in this proposal for normal and SIV-infected Rh and AGMs, to confirm the existence of functional Tregs and to verify our ability to manipulate this T cell subset. We propose the following Specific Aims (SA): SA1: To characterize Tregs in normal and SIV-infected Rh and AGMs. CD25 is not a specific marker for Tregs; it is also upregulated upon conventional T cell activation. Our proposal will therefore focus on identification of specific markers for Tregs such as FOXP3, GITR, CD223 and neuropilin-1 in association with previously studied CD4+CD25+ T cells and also on determining the in vitro suppressive functions of T cell subsets identified with these markers, that have never been studied in non-human primates (NHP). SA2: To determine the distribution of Tregs in tissues of normal and SIV-infected Rh and AGMs. CD4+CD25+ cells from peripheral blood might represent only a small portion of the total Tregs. In order to focus our future SIV studies, we intend to determine the density and function of Tregs in lymph nodes (LNs), lung and intestine in both Rh and AGMs. SA3: To verify the ability of available anti-CD25 blocking/depleting drugs to eliminate Tregs in Rh and AGMs. Elimination of Tregs or Treg function in SIV-infected Rh and AGMs will enhance our knowledge about the role of this T cell subset in pathogenic and non-pathogenic SIV infections. If this specific aim will establish that this experiment is possible in normal NHPs, we will further assess the impact of Treg depletion on viral replication in chronically SIVagm-infected AGMs. Combined, these aims are designed to characterize and manipulate simian Tregs. This data will be critical for future studies examining the role of these cells in AIDS pathogenesis and may also open numerous avenues for the study of Tregs in other infectious or immune diseases for which Rh and AGMs are used as models.

描述（由申请人提供）：该项目的目的是检查恒河猴 (Rh) 和非洲绿猴 (AGM) 中的 T 调节细胞 (Treg)。 Tregs 最初定义为 CD4+CD25+，可抑制小鼠和人类的 T 细胞活化和增殖。由于 T 细胞的慢性免疫激活和快速周转是人类和 Rh 中致病性 HIV/SIVmac 感染的标志，因此这些细胞可能在 HIV/SIV 发病机制中发挥重要作用。 Rh 和 AGM 是研究 SIV 发病机制的最佳模型，它们在一个基本方面有所不同：Rh 感染的 SIVmac 会发展为艾滋病，而感染 SIVagm 的 AGM 通常保持健康。我们的初步研究表明，SIVmac 感染的 Rh 中 CD4+CD25+ T 细胞丢失，这可能解释了这种病原性感染中描述的异常慢性 T 细胞过度激活。相比之下，我们发现在 SIVagm 感染的非常早期阶段，Treg 数量有所增加，并且在长期感染 SIVagm 的 AGM 中 CD4+CD25+ T 细胞得到更好的保存。 SIVagm 感染的 AGM 中 CD4+CD25+ T 细胞动力学模式证实了自然宿主在 SIV 感染期间缺乏免疫激活和周转。因此，我们假设功能齐全的 Tregs 存在于非人灵长类动物中，并且可能在 SIV 感染中发挥保护作用。为了清楚地定义Tregs在致病性和非致病性SIV感染中的作用，我们在本提案中针对正常和SIV感染的Rh和AGM设计了实验，以确认功能性Tregs的存在并验证我们操纵该T细胞亚群的能力。我们提出以下具体目标 (SA)： SA1：表征正常和 SIV 感染的 Rh 和 AGM 中的 Tregs。 CD25 不是 Tregs 的特异性标志物；它在常规 T 细胞激活时也会上调。因此，我们的提案将重点关注与先前研究的 CD4+CD25+ T 细胞相关的 Tregs 特异性标记物的鉴定，例如 FOXP3、GITR、CD223 和 Neuropilin-1，并确定用这些标记物鉴定的 T 细胞亚群的体外抑制功能，从未在非人类灵长类动物（NHP）中进行过研究。 SA2：确定Tregs在正常和SIV感染的Rh和AGM组织中的分布。来自外周血的 CD4+CD25+ 细胞可能仅占总 Tregs 的一小部分。为了集中我们未来的 SIV 研究，我们打算确定 Rh 和 AGM 中淋巴结 (LN)、肺和肠中 Tregs 的密度和功能。 SA3：验证可用的抗 CD25 阻断/消耗药物消除 Rh 和 AGM 中 Tregs 的能力。消除 SIV 感染的 Rh 和 AGM 中的 Tregs 或 Treg 功能将增强我们对该 T 细胞亚群在致病性和非致病性 SIV 感染中的作用的了解。如果这一具体目标能够证明该实验在正常 NHP 中是可能的，我们将进一步评估 Treg 耗竭对慢性 SIVagm 感染的 AGM 中病毒复制的影响。综合起来，这些目标旨在表征和操纵猿猴 Tregs。这些数据对于未来研究这些细胞在艾滋病发病机制中的作用至关重要，也可能为研究 Tregs 在其他感​​染或免疫疾病（以 Rh 和 AGM 为模型）中的研究开辟多种途径。