METH-induced T cell Dysfunction: Role in HIV-1 Immunopathogenesis

METH 诱导的 T 细胞功能障碍：在 HIV-1 免疫发病机制中的作用

基本信息

批准号：
7556633
负责人：
Raghava Potula
金额：
$ 22.5万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-09-15 至 2010-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7556633
关键词：
3-nitrotyrosine 76-kDa SH2 domain-containing leukocyte protein Acetates Adaptor Signaling Protein Address Affect Alcohol abuse American Animal Model Antigens Antioxidants Applications Grants Biological Assay Biological Markers CD3 Antigens CD8B1 gene Cell Differentiation process Cell Proliferation Cell physiology Cell surface Cells Central Nervous System Infections Chronic Communicable Diseases Condition Cultured Cells Cytokine Gene Cytotoxic T-Lymphocytes DNA Data Defect Disease Progression Distal Encephalitis Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Event Extracellular Signal Regulated Kinases Flow Cytometry Functional disorder Gene Chips Gene Expression Generations Genes Glutathione HIV HIV Infections HIV-1 Host resistance Human Illicit Drugs Immune Immune Cell Activation Immune System Diseases Immune response Immune system Immunity Immunosuppression In Vitro Incidence Infection Inflammation Interferons Interleukin-10 Interleukin-2 Interleukin-4 Investigation Ionomycin LCP2 gene Lead Levocarnitine Acetyl Link Lipids Longevity Measures Mediating Membrane Potentials Membrane Proteins Methamphetamine Microarray Analysis Mitochondria Mitogen-Activated Protein Kinases Modeling Molecular Molecular Profiling Monoclonal Antibody HuM291 Morbidity - disease rate Muromonab-CD3 NF-AT Neuraxis Nitric Oxide Organ Oxidative Stress Pathway interactions Peripheral Pharmaceutical Preparations Phosphorylation Play Polymerase Chain Reaction Population Predisposition Production Proteins Public Health RNA Reaction Reactive Oxygen Species Receptor Activation Receptor Signaling Regulation Resort Resveratrol Reverse Transcriptase Polymerase Chain Reaction Role Sampling Serum Signal Pathway Signal Transduction Signaling Molecule Splenocyte Staining method Stains Study models System T Cell Receptor Signaling Pathway T-Cell Activation T-Cell Proliferation T-Cell Receptor T-Lymphocyte Testing Therapeutic Thinking Time Tissues Transcriptional Activation Transforming Growth Factors Translating Tumor Necrosis Factor-alpha Tumor Necrosis Factors Viral Viral Load result Virus Western Blotting Work ZAP-70 Gene astrogliosis base catalase cell mediated immune response chemokine clinically significant concept crosslink cytokine cytotoxic design drug abuser functional status granzyme B human MAPK14 protein human TNF protein immune function improved in vivo inhibitor/antagonist insight interest kinase inhibitor macrophage methamphetamine exposure neuroinflammation neuropathology neurotoxicity novel nuclear factors of activated T-cells perforin phorbol-12-myristate prevent psychostimulant response stimulant abuse stress-activated protein kinase 1 transcription factor

项目摘要

DESCRIPTION (provided by applicant): Illicit drugs such as methamphetamine (METH) alter immune functions and decreases host resistance. There is an association between METH abuse and enhanced susceptibility to infections; however, underlying mechanisms are largely unknown. High incidence of HIV-1 infection in METH abusers and potential effects of METH on immune system underscore clinical significance of METH-HIV-1 co-morbidity. Defective immune responses could lead to the accelerated HIV-1 infection in the peripheral organs and central nervous system (CNS). Preliminary data point to the oxidative stress as one of possible causes of METH induced immune dysfunction. Indeed, our preliminary studies indicate that METH exposure elicits oxidative stress in T cells and upon T-cell receptor stimulation show T cell proliferation and decreases cytokine production. T cells exposed to METH demonstrate modulation of genes controlling in immune cell activation and T cell surface markers. Therefore, we hypothesize that the oxidative stress caused by METH in T lymphocytes dampens immune responses, impairs T cell activation and proliferation leading to enhanced progression of HIV-1 infection. Using a combination of in vitro systems and animal model for HIV-1 encephalitis chronically exposed to METH, we will address the following questions: (1) What are the potential implications of METH- induced oxidative stress on T cell functions? (2) What are the mechanisms underlying impaired T cell immune responses mediated by oxidative stress associated with METH? (3) How does T cell dysfunction affect the adaptive immune system responses to HIV-1 infection in and outside of CNS? Antioxidants and specific signaling inhibitors will be utilized to delineate pathways involved in these effects. We believe that the proposed works are highly significant as they will uncover novel mechanisms mediating combined effects of HIV-1 and METH abuse on immunity and propose therapeutic approaches based on these investigations. PUBLIC HEALTH RELEVANCE Methamphetamine is a highly addictive stimulant abused by millions of Americans and is known to alter immune function and increase susceptibility to infection. Epidemiological studies indicate growing evidence of the association between METH abuse and an increased incidence of HIV-1 infections. However, the apparent causal interrelationship between METH abuse and susceptibility to HIV-1 infection or its progression are largely unknown. This proposal aims to understand putative mechanisms of immune dysfunctions in the setting of METH abuse and HIV-1 infection.

描述（由申请人提供）：甲基苯丙胺 (METH) 等非法药物会改变免疫功能并降低宿主抵抗力。滥用冰毒与感染易感性增加之间存在关联；然而，根本机制在很大程度上尚不清楚。 METH 滥用者中 HIV-1 感染的高发生率以及 METH 对免疫系统的潜在影响强调了 METH-HIV-1 共病的临床意义。免疫反应缺陷可能导致外周器官和中枢神经系统 (CNS) 加速 HIV-1 感染。初步数据表明，氧化应激是冰毒引起的免疫功能障碍的可能原因之一。事实上，我们的初步研究表明，冰毒暴露会引起 T 细胞的氧化应激，并且在 T 细胞受体刺激后显示 T 细胞增殖并减少细胞因子的产生。暴露于冰毒的 T 细胞表现出控制免疫细胞激活和 T 细胞表面标记的基因的调节。因此，我们推测 METH 在 T 淋巴细胞中引起的氧化应激会抑制免疫反应，损害 T 细胞的活化和增殖，从而导致 HIV-1 感染的加速进展。结合使用体外系统和长期暴露于冰毒的 HIV-1 脑炎动物模型，我们将解决以下问题：（1）冰毒诱导的氧化应激对 T 细胞功能的潜在影响是什么？ (2) 与 METH 相关的氧化应激介导的 T 细胞免疫反应受损的机制是什么？ (3) T细胞功能障碍如何影响中枢神经系统内外的适应性免疫系统对HIV-1感染的反应？抗氧化剂和特定信号抑制剂将用于描绘这些效应所涉及的途径。我们相信，拟议的工作非常重要，因为它们将揭示介导 HIV-1 和 METH 滥用对免疫的综合影响的新机制，并根据这些研究提出治疗方法。公共卫生相关性甲基苯丙胺是一种高度成瘾的兴奋剂，被数百万美国人滥用，已知会改变免疫功能并增加感染的易感性。流行病学研究表明，越来越多的证据表明冰毒滥用与 HIV-1 感染发病率增加之间存在关联。然而，METH 滥用与 HIV-1 感染或其进展易感性之间的明显因果关系在很大程度上尚不清楚。该提案旨在了解 METH 滥用和 HIV-1 感染情况下免疫功能障碍的假定机制。