Effects of IL-6 blockade in treated HIV infection

IL-6 阻断对 HIV 感染治疗的影响

基本信息

批准号：
8617799
负责人：
MICHAEL MARCEL LEDERMAN
金额：
$ 119.07万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-13 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8617799
关键词：
Antiviral Agents Antiviral Therapy Apoptotic Attenuated Automobile Driving BCL2 gene Biological Assay Blood Vessels Carnitine Cell Cycle Cell Death Cells Coagulation Process Data Disease Dose Down-Regulation Exposure to Failure Gene Expression Profile General Population Genetic HIV HIV Infections HIV-1 Heart Homing Human IL7R gene Immune Immune system Infection Inflammation Inflammation Mediators Inflammatory Insulin Insulin Resistance Integrins Interferons Interleukin-17 Interleukin-6 Interleukin-7 Intervention Studies Leukocytes Link Lipids Lymphocyte Mediating Metabolism Modeling Monitor Monoclonal Antibodies Morbidity - disease rate Mucous Membrane Myelogenous Pathogenesis Pathologic Pathway interactions Patients Persons Pharmaceutical Preparations Plasma Population Genetics Positioning Attribute Proteins Rheumatoid Arthritis Role Signal Transduction Sorting - Cell Movement Source System T cell response T-Lymphocyte T-Lymphocyte Subsets Testing Thromboplastin Time brachial artery cardiovascular risk factor cell type clinically relevant cytokine disorder risk heart disease risk improved in vivo indexing inflammatory marker inhibitor/antagonist interleukin-22 intervention effect lipid metabolism memory CD4 T lymphocyte metabolomics microbial monocyte mortality novel oxidized lipid oxidized low density lipoprotein peripheral blood public health relevance receptor resistin restoration success transcriptomics

项目摘要

DESCRIPTION (provided by applicant): We have shown that plasma levels of IL-6 are perhaps the most robust predictors of morbidity and mortality in treated HIV-1 infection. The overall objective of this interventional study is to establish the position of heightened IL-6 exposure on the pathways of pathogenesis and morbidity in treated HIV-1 infected persons with immune failure. We propose 3 aims: I. To examine the effects of IL-6 inhibition on the pathogenesis of immune failure and inflammation in treated HIV infection. Our preliminary data have led us to a novel model of HIV immunopathogenesis where the damaged gut is both the source of high levels of IL-6 and where local and systemic exposure to IL-6 sustains the gut mucosal barrier breach and impairs immune restoration even in the presence of antiviral therapy. This is caused by IL-6 mediated inhibition of the IL-7 receptor ¿ chain - CD127 and IL-6-mediated activation of central memory CD4 T cell cycling and death. We hypothesize that administration of the IL-6 receptor antagonist tocilizumab will decrease the pathologic central memory CD4 T cell cycling and will also restore systemic and gut T cell responses to the homeostatic cytokine IL-7. In the gut and systemically, we will examine the restoration of immune cells, their expression of CD127 and the pro- survival bcl-2 and the gut homing molecule ¿4¿7 that IL-7 induces, the ability of gut cells to express the gut protective molecules IL-22, IL-17 and the effects of this intervention on local and systemic indices of gut mucosal barrier integrity. II. To examine the effect of systemic IL-6 inhibition on indices of cardiovasculr disease (CVD) risk in treated HIV-1 infection. Increased IL-6 levels have been associated with CVD risk in HIV-1 infection and in the general population and genetic studies also demonstrate a role for IL-6 in CVD risk. During IL-6 receptor blockade, we will monitor blood vessel function, levels of insulin resistance, inflammatory lipids and levels of inflammatory and patrolling monocytes that express the clot forming tissue factor. We will relate them to the effects of IL-6 inhibition on targeted inflammatory markers to be studied in Sp Aim 1 and to the activation pathways that comprise the transcriptomic and metabolomic approaches in Sp Aim 3. III. To examine the effects of systemic IL-6 inhibition on the inflammatory transcriptome and plasma metabolomes in treated HIV-1 infection. Our detailed transcriptional analysis of circulating white blood cells in immune failure patients has found a proinflammatory signature reflective of increased IL-6 exposure and also a strong type 1 interferon signature. At the same time the plasma metabolome in immune failure is consistently distinguishable from those of immune successes and healthy controls with profound perturbations in lipid metabolism with the greatest abnormalities seen in subjects with the highest plasma IL-6 levels. We will examine the effects of IL-6 receptor blockade on the peripheral blood leukocyte transcriptome and plasma metabolome and relate these to functional assays of immune pathogenesis and cardiovascular risk.

描述（由适用提供）：我们已经表明，IL-6的血浆水平可能是治疗的HIV-1感染中发病率和死亡率最强的预测指标。这项介入研究的总体目的是确定IL-6暴露于免疫衰竭的受HIV-1感染者的发病机理和发病率的途径。我们提出3个目标：I。检查IL-6抑制对治疗的HIV感染中免疫衰竭和感染的发病机理的影响。我们的初步数据使我们建立了一种新型的HIV免疫病变模型，其中受损的肠道既是IL-6的高水平来源，又是IL-6的局部和全身暴露，即使在存在抗病毒治疗的情况下，局部和全身暴露于肠道粘膜屏障违规并会损害免疫治疗。这是由IL-6介导的对IL-7受体 - 链-CD127和IL-6介导的中央记忆CD4 T细胞循环和死亡激活的抑制作用引起的。我们假设给药IL-6受体拮抗剂Tocilizumab将减少病理中心记忆CD4 T细胞循环，并且还将恢复对稳态细胞因子IL-7的全身和肠细胞反应。在肠道和系统上，我们将检查免疫细胞的恢复，CD127的表达和促生存的Bcl-2和肠道归巢分子»4€7，即IL-7会影响IL-7的影响，肠道细胞表达肠道保护性分子IL-22，IL-22，IL-17，IL-17，IL-17，IL-17及其对局部和系统性intecier intecier Indice nimuc的影响。 ii。检查全身IL-6抑制对治疗的HIV-1感染中心血管疾病（CVD）风险指标的影响。 IL-6水平升高与HIV-1感染中的CVD风险有关，在一般人群中，遗传研究也证明了IL-6在CVD风险中的作用。在IL-6受体阻滞期间，我们将监测血管功能，胰岛素抵抗水平，炎症性脂质以及表达凝块形成组织因子的炎症和巡逻的单核细胞的水平。我们将与IL-6抑制对SP AIM 1中的靶向炎症标记的影响以及构成SP AIM 3. III中转录组和代谢组方法的激活途径有关。检查全身IL-6抑制对治疗的HIV-1感染中炎症转录组和血浆代谢组的影响。我们对免疫衰竭患者循环白细胞的详细转录分析发现，促炎的特征反映了IL-6暴露的增加以及强大的1型干扰特征。同时，免疫衰竭中的血浆代谢组与免疫成功和健康对照的血浆代谢组在脂质代谢中具有深远的扰动，在具有最高血浆IL-6水平的受试者中，具有最大的异常。我们将检查IL-6受体阻滞对外周血白细胞转录组和等离子体代谢组的影响，并将其与免疫发病发生和心血管风险的功能测定有关。