Dendritic Cell Dynamics in Peripheral and Lymphoid Tissues in SIV Infection

SIV 感染时外周组织和淋巴组织中的树突状细胞动力学

基本信息

批准号：
7385998
负责人：
Simon M Barratt-Boyes
金额：
$ 46.94万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-04-01 至 2012-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7385998
关键词：
Accounting Acquired Immunodeficiency Syndrome Animals Antigen-Presenting Cells Antigens Antiviral Agents Apoptosis Binding Biological Assay Blood Blood Circulation Bone Marrow CD34 gene CD4 Positive T Lymphocytes Cell Count Cell Cycle Kinetics Cells Cellular biology Cessation of life Chronic Complex Data Dendritic Cells Dendritic cell activation Disease Enzyme-Linked Immunosorbent Assay Epidermis Family Flow Cytometry Frequencies Generations HIV-1 Hematopoiesis Homeostasis Human Immune Immune response Immunity Immunofluorescence Immunologic In Situ In Vitro Individual Infection Inflammation Inflammatory Interferon Type I Interferons Label Lead Ligands Link Lymphatic Lymphoid Lymphoid Tissue Macaca mulatta Measures Mediating Mesentery Modeling Monkeys Mucous Membrane Myelogenous Numbers Peripheral Play Polymerase Chain Reaction Population Process Production Recovery Research Personnel Role SIV Simian Acquired Immunodeficiency Syndrome Skin Source Spleen Staging Staining method Stains Suspension substance Suspensions T-Lymphocyte TNF-related apoptosis-inducing ligand TNFRSF10A gene TNFRSF10B gene Testing Therapeutic Thinking Time Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Viremia Virus Virus Diseases antiretroviral therapy cytokine density human TNF protein lymph nodes nonhuman primate novel pathogen peripheral blood receptor trafficking transmission process tumor necrosis factor receptor 1A

项目摘要

DESCRIPTION (provided by applicant): Dendritic cells (DC) are professional antigen-presenting cells that are critical in the innate and acquired immune response to pathogens. DC exist as two major subsets in humans and nonhuman primates, being classical or myeloid DC (mDC) and plasmacytoid DC (pDC). mDC and pDC are lost from the circulation in human immunodeficiency virus type 1 (HIV)-infected individuals, which is thought to be due to recruitment of circulating cells to lymphoid tissues and is associated with progression to disease. The proposed recruitment of pDC to lymph nodes has been used to explain the increased expression of IFN-a in lymph nodes in HIV- infected individuals, which in turn has been linked to TNF-related apoptosis-inducing ligand (TRAIL)-mediated CD4+ T cell apoptosis. However, the effects of infection on DC subsets in lymphoid tissues remain largely unexplored. Using the rhesus macaque/simian immunodeficiency virus (SIV) model, we have shown that DC numbers are increased in lymph nodes at the peak of viremia, consistent with recruitment through inflammation. However, during simian AIDS, DC are depleted from blood, peripheral and mesenteric lymph nodes and spleen, and are reduced in density in skin. These data suggest a highly dynamic process of DC recruitment to and subsequent loss from lymphoid tissues during SIV infection. Our proposal aims to build on these novel findings, focusing in particular on the mechanism(s) of DC loss. Our preliminary data indicate that lymph node DC in monkeys with AIDS are activated and prone to spontaneous death in culture. We hypothesize that DC loss from lymphoid tissues during pathogenic SIV infection is primarily mediated by factors relating to chronic inflammation and activation. To test this hypothesis we will comprehensively analyze DC subsets in blood and tissues after intravaginal inoculation of rhesus macaques with SIVmac251. We will administer antiretroviral therapy (ART) in a subset of animals, which will aid in dissecting the mechanism of cell loss by reducing immune activation. We will (1) Determine DC kinetics and activation and the relationship to tissue inflammation in SIV infection; (2) Determine the role of direct infection in DC loss in SIV infection; (3) Determine the role of apoptosis in DC loss during SIV infection and (4) Determine the capacity for pDC and mDC to produce IFN-a and Th1-stimulating cytokines during SIV infection. These studies will greatly advance our understanding of complex DC biology in HIV infection.

描述（由申请人提供）：树突状细胞（DC）是专业的抗原呈递细胞，在针对病原体的先天和获得性免疫反应中至关重要。 DC 在人类和非人灵长类动物中以两个主要亚型存在，即经典或髓样 DC (mDC) 和浆细胞样 DC (pDC)。 mDC 和 pDC 在人类免疫缺陷病毒 1 型 (HIV) 感染者的循环中丢失，这被认为是由于循环细胞募集到淋巴组织所致，并且与疾病进展有关。拟议的 pDC 向淋巴结的募集已被用来解释 HIV 感染个体淋巴结中 IFN-a 表达的增加，而这又与 TNF 相关凋亡诱导配体 (TRAIL) 介导的 CD4+ T 有关。细胞凋亡。然而，感染对淋巴组织中 DC 亚群的影响在很大程度上仍未被探索。使用恒河猴/猿猴免疫缺陷病毒（SIV）模型，我们发现，在病毒血症高峰期，淋巴结中的 DC 数量增加，这与炎症引起的招募一致。然而，在猿猴艾滋病期间，DC从血液、外周和肠系膜淋巴结以及脾中耗尽，并且皮肤中的密度降低。这些数据表明，在 SIV 感染期间，DC 募集到淋巴组织并随后从淋巴组织中流失是一个高度动态的过程。我们的提案旨在以这些新颖的发现为基础，特别关注直流损耗的机制。我们的初步数据表明，患有艾滋病的猴子的淋巴结 DC 被激活，并且在培养物中易于自发死亡。我们假设致病性 SIV 感染期间淋巴组织中 DC 的丢失主要是由与慢性炎症和激活相关的因素介导的。为了检验这一假设，我们将全面分析恒河猴阴道内接种 SIVmac251 后血液和组织中的 DC 亚群。我们将对一部分动物进行抗逆转录病毒治疗（ART），这将有助于通过减少免疫激活来剖析细胞损失的机制。我们将 (1) 确定 SIV 感染中 DC 动力学和激活以及与组织炎症的关系； (2)确定直接感染在SIV感染中DC丢失中的作用； (3) 确定细胞凋亡在 SIV 感染期间 DC 丢失中的作用，以及 (4) 确定 SIV 感染期间 pDC 和 mDC 产生 IFN-a 和 Th1 刺激细胞因子的能力。这些研究将极大地增进我们对 HIV 感染中复杂的 DC 生物学的理解。