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：
7923493
负责人：
Simon M Barratt-Boyes
金额：
$ 16.78万
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：
2009
资助国家：
美国
起止时间：
2009-09-22 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7923493
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 Peripheral Play 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 Time Tissues Tumor Necrosis Factor-alpha Tumor Necrosis Factors Viremia Virus Virus Diseases antiretroviral therapy cytokine density 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，在先天和获得的免疫反应中至关重要。 DC作为人类和非人类灵长类动物的两个主要子集存在，是经典或髓样DC（MDC）和浆细胞类动物DC（PDC）。 MDC和PDC因人类免疫缺陷病毒1型（HIV）感染的个体的循环而丢失，这被认为是由于将循环细胞募集到淋巴组织组织而引起的，并且与疾病的发展有关。提出的PDC募集到淋巴结中已被用来解释艾滋病毒感染个体中淋巴结中IFN-A的表达增加，这又与TNF与TNF相关的凋亡诱导配体（TRAIL）介导的CD4+ T细胞凋亡有关。然而，感染对淋巴组织中DC亚群的影响仍然在很大程度上尚未探索。使用恒河猕猴/替代型免疫缺陷病毒（SIV）模型，我们已经表明，在病毒血症峰值的淋巴结中，直流数量增加，这与通过炎症的募集一致。但是，在猿猴艾滋病期间，DC从血液，外周和肠系膜淋巴结和脾脏中耗尽，并降低了皮肤密度。这些数据表明，在SIV感染期间，DC募集的高度动态过程以及随后因淋巴组织的损失。我们的建议旨在基于这些新颖的发现，尤其是针对DC损失的机制。我们的初步数据表明，用艾滋病的猴子中的淋巴结直流被激活，容易在培养中自发死亡。我们假设病原SIV感染期间淋巴组织的直流损失主要是由与慢性炎症和激活有关的因素介导的。为了检验这一假设，我们将在用SIVMAC251的恒河猴猕猴膀胱内接种后血液和组织中全面分析DC亚群。我们将在动物子集中进行抗逆转录病毒疗法（ART），这将有助于通过减少免疫激活来解剖细胞损失的机理。我们将（1）确定DC动力学和激活以及SIV感染中与组织炎症的关系；（2）确定直接感染在DC损失中的作用；（3）确定凋亡在SIV感染期间DC丧失中的作用，（4）确定PDC和MDC在SIV感染过程中产生IFN-A和Th1刺激细胞因子的能力。这些研究将大大提高我们对HIV感染中复杂DC生物学的理解。