Mechanisms of Th17 and Treg cell dysregulation in oral mucosal inflammation during HIV disease

HIV疾病期间口腔粘膜炎症中Th17和Treg细胞失调的机制

基本信息

批准号：
9320339
负责人：
Pushpa Pandiyan
金额：
$ 30.89万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-04-01 至 2022-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9320339
关键词：
Affect Anatomy Anti-Inflammatory Agents Anti-Retroviral Agents Anti-inflammatory Area Blood CD14 gene CD4 Positive T Lymphocytes Cause of Death Cell Count Cell Death Cell Death Induction Cell physiology Cells Chronic Clinical Comprehension Data Dentists Disease Equilibrium FOXP3 gene Frequencies Functional disorder Funding Gingiva Goals HIV HIV Infections Heterogeneity Histone Acetylation Human IRAK1 gene Immune Immune System Diseases Immune System and Related Disorders Immune signaling Immune system Immunity Immunologics Immunology In Vitro Individual Infection Inflammation Inflammatory Interferon Type II Interleukin-6 Intervention KLRB1 gene Lead Lesion Ligands Light Link Location Lymphoid Tissue Measures Mediating Microbe Mucositis Mucous Membrane Nature Oral Oral Manifestations Oral Pathology Oral mucous membrane structure Pathogenesis Pathogenicity Patients Periodontitis Peripheral Pharmaceutical Preparations Plasma Play Proto-Oncogene Proteins c-akt Public Health Publications Receptor Signaling Regulatory T-Lymphocyte Research Research Personnel Research Priority Residual state Role SIV STAT3 gene Saliva Sampling Signal Transduction Symbiosis T-Lymphocyte TLR2 gene TLR4 gene TLR6 gene TNF gene Thinking Thymus Gland Tissues Toll-like receptors Tonsil Tonsillar Tissue United States National Institutes of Health Viral Load result Viral reservoir Virus Diseases antiretroviral therapy cytokine frontier histone methylation immune activation immunoregulation insight malignant mouth neoplasm microbial mortality multidisciplinary next generation novel novel marker novel therapeutics oral microbiome oral tissue pathogen prevent programs receptor transcriptome sequencing virology

项目摘要

ABSTRACT Residual oral inflammation along with chronic systemic immune activation is an important feature in many (HIV)/Combined Antiretroviral therapy (cART) patients, and has been linked to a wide range of oral pathologies including periodontitis, erythematous candidal lesions, viral infections and oral cancer. Although cART can suppress plasma viral loads to undetectable levels, increased mortality is closely associated with mucosal immune dysbiosis and persistent viral reservoirs in lymphoid tissues. To date, however, the majority of research on immune activation has been derived from analysis of circulating quiescent T cells. How microbial products from altered oral microbiome and opportunistic pathogens contribute to immune cell alterations and oral mucosal dysbiosis is unknown. A better comprehension of this phenomenon, and various interactions between immune cells, commensal and pathogenic microbes is needed to shed light on HIV-mediated immune oral immune dysfunction. Our proposal will investigate these interactions with a specific focus on Th17 cells and Tregs, the critical subsets of CD4+ T lymphocytes that play crucial roles in maintaining the mucosal barrier integrity and preventing inflammation respectively. We hypothesize that loss of oral Th17 cells and increase in proportions of dysfunctional Tregs contribute to residual oral inflammation in HIV+ patients. We will determine the functions of interventional IL-21 in restoring Th17 cells during HIV infection. We will also define the role of TLR signaling and IL-6 in inducing Treg plasticity, generating dysfunctional Tregs and contributing to oral immune pathogenesis of HIV+ individuals. These studies will contribute to new ways of thinking about oral inflammation in HIV+ individuals, and aid in generating novel therapeutic strategies to manage HIV mediated chronic oral dysbiosis. This multidisciplinary project supported by a robust procurement network for human tonsillar and oral tissues from HIV+ individuals will enable an unprecedented insight into HIV dependent oral mucosal inflammatory mechanisms, and is compatible with Trans-NIH FY-2016 funding priorities for HIV research that states “Study the effect of the CD4+ T-cell pool heterogeneity in terms of differentiation .. lineage (Th1, Th2, Th17, Treg, Tfh), anatomic location (blood versus lymphoid tissues versus mucosal tissues)”, as area of research priority. Most importantly, by defining the immune plasticity mechanisms in Th17 cells and Tregs during HIV+/SIV infection, the project fits well with the program objectives for RFA-DE-17-006.

抽象的残留的口腔炎症以及慢性全身免疫激活是许多疾病的一个重要特征。 (HIV)/联合抗逆转录病毒治疗 (cART) 患者，并与多种口腔疾病有关包括牙周炎、红斑念珠菌病变、病毒感染和口腔癌。将血浆病毒载量抑制至不可检测的水平，死亡率增加与粘膜病毒密切相关然而，迄今为止，大多数病毒都存在于淋巴组织中的免疫失调和持续病毒库。免疫激活的研究源自对循环静止 T 细胞的微生物作用的分析。口腔微生物组和机会性病原体的产物有助于免疫细胞的改变和口腔粘膜生态失调尚不清楚，目前尚不清楚如何更好地理解这种现象以及各种相互作用。需要了解免疫细胞、共生微生物和病原微生物之间的关系，以阐明艾滋病毒介导的免疫我们的提案将特别关注 Th17 细胞来研究这些相互作用。和 Tregs，CD4+ T 淋巴细胞的关键亚群，在维持粘膜屏障方面发挥着至关重要的作用我们分别对抗口腔 Th17 细胞的损失和增加。我们将确定 HIV+ 患者中功能失调的 Tregs 的比例会导致残留的口腔炎症。干预性 IL-21 在 HIV 感染期间恢复 Th17 细胞中的功能我们还将定义其作用。 TLR 信号传导和 IL-6 诱导 Treg 可塑性、产生功能失调的 Tregs 并有助于口腔免疫这些研究将有助于对口腔炎症进行新的思考。 HIV+个体，并帮助制定新的治疗策略来管理 HIV 介导的慢性口腔疾病生态失调。这个多学科项目得到了强大的人类扁桃体和口腔采购网络的支持来自 HIV+ 个体的组织将使人们对 HIV 依赖性口腔粘膜有前所未有的了解炎症机制，并且与 Trans-NIH 2016 财年 HIV 研究资助优先事项相一致指出“研究 CD4+ T 细胞库异质性对分化的影响..谱系（Th1、Th2、 Th17、Treg、Tfh），解剖位置（血液、淋巴组织、粘膜组织）”，作为区域最重要的是，通过定义 Th17 细胞和 Tregs 的免疫可塑性机制。 HIV+/SIV 感染，该项目非常符合 RFA-DE-17-006 的计划目标。