Depletion of myeloid-derived suppressor cells (MDSCs) in HIV-1-infection

HIV-1 感染中骨髓源性抑制细胞 (MDSC) 的耗竭

基本信息

批准号：
7841378
负责人：
Zdenek Hel
金额：
$ 18.31万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-07-07 至 2012-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7841378
关键词：
Acute Address Autoimmune Diseases Autologous B-Lymphocytes Bacterial Infections Biopsy Blood CCR5 gene CD14 gene CD209 gene CD4 Positive T Lymphocytes CD8B1 gene CXCR4 gene Cell Count Cells Cellular Immunity Characteristics Chronic Data Disease Enterocolitis Failure Feedback Frequencies Gut associated lymphoid tissue HIV-1 Highly Active Antiretroviral Therapy Homeostasis ITGAM gene Immune Immunosuppressive Agents In Vitro Incidence Individual Infection Inflammation Inflammatory Bowel Diseases Intestines Lobular Neoplasia Malignant Neoplasms Mucous Membrane Myelogenous Nitric Oxide Oxides Pathogenesis Patients Population Process Production Reactive Oxygen Species Regulatory T-Lymphocyte Role Serum Staging Suppressor-Effector T-Lymphocytes T cell response T-Cell Activation T-Lymphocyte Testing Tissues Trauma Viral Viral Load result arginase base design exhaustion gastrointestinal immune activation microbial mouse model novel novel therapeutics prevent public health relevance rectal regenerative

项目摘要

DESCRIPTION (provided by applicant): Myeloid-derived suppressor cells (MDSCs) is a recently characterized population of cells that expands during cancer, infection, inflammation, and trauma. MDSCs display a remarkable ability to suppress T cell-mediated immunity by multiple mechanisms including production of arginase 1, reactive oxygen species, nitric oxide, and induction of regulatory T cells. MDSCs represent an important regulatory feedback immune mechanism preventing exaggerated chronic inflammation in the context of various diseases. HIV-1 infection is characterized by chronic activation and rapid turnover of CD4+ and CD8+ T cells. Recently obtained evidence suggests that HIV-1 infection is associated with chronic inflammation in the gastrointestinal mucosal tissue and a translocation of microbial products to the systemic compartment where they contribute to T cell activation. Activation-driven exhaustion of CD4+ T cell regenerative capability eventually leads to the collapse of CD4+ T cell homeostasis. Precise characterization of the mechanisms underlying chronic T cell activation is central to the understanding of HIV-1 pathogenesis. It would be expected that chronic immune activation associated with HIV-1 infection would result in a significant expansion of MDSC population as observed in other viral and bacterial infections. Surprisingly, our preliminary data demonstrate that the frequency of circulating MDSCs is significantly reduced in HIV-1-infected patients, particularly patients not treated with highly active anti-retroviral therapy (HAART). Absence of this important regulatory population that normally restricts harmful immune activation may significantly contribute to the uncontrolled chronic inflammation in the systemic compartment and intestinal mucosal tissue and to the high incidence of autoimmune disorders observed in HIV-1-infected individuals. We will address the role of MDSCs in HIV-1 infection in three specific aims: 1) Determine whether the frequency of MDSCs is reduced in the blood and intestinal tissue of HIV-1-infected individuals; 2) Determine whether MDSCs can be directly infected with HIV-1; and 3) Determine whether MDSCs in HIV-1- infected patients preserve their immunosuppressive activity. Elucidation of the role of MDSCs in HIV-1 infection may be instrumental in the design of novel therapeutic strategies based on controlled expansion of MDSC population resulting in a suppression of chronic immune activation in HIV-1-infected patients. PUBLIC HEALTH RELEVANCE: In this application we present a novel observation that HIV-1 infection is associated with a severe depletion of myeloid-derived suppressor cells (MDSCs) and hypothesize that the absence of this important immunoregulatory population significantly contributes to the chronic immune activation resulting in the gradual decline of CD4+ T cells. Precise characterization of mechanisms underlying chronic T cell activation is central to our understanding of HIV-1 pathogenesis. Elucidation of the role of MDSCs in HIV-1 infection may be instrumental in the design of novel therapeutic strategies based on controlled expansion of MDSC population resulting in a suppression of chronic immune activation in HIV-1-infected patients.

描述（由申请人提供）：骨髓源性抑制细胞（MDSC）是最近表征的细胞群，其在癌症、感染、炎症和创伤期间扩增。 MDSC 显示出通过多种机制抑制 T 细胞介导的免疫的非凡能力，包括产生精氨酸酶 1、活性氧、一氧化氮和诱导调节性 T 细胞。 MDSC 代表了一种重要的调节反馈免疫机制，可防止各种疾病中过度的慢性炎症。 HIV-1 感染的特点是 CD4+ 和 CD8+ T 细胞的慢性激活和快速更新。最近获得的证据表明，HIV-1 感染与胃肠道粘膜组织的慢性炎症以及微生物产物易位至全身区室相关，在系统区室中它们有助于 T 细胞激活。激活驱动的 CD4+ T 细胞再生能力耗尽最终导致 CD4+ T 细胞稳态崩溃。慢性 T 细胞激活机制的精确表征对于理解 HIV-1 发病机制至关重要。预计与 HIV-1 感染相关的慢性免疫激活将导致 MDSC 群体显着增加，正如在其他病毒和细菌感染中观察到的那样。令人惊讶的是，我们的初步数据表明，HIV-1感染患者中循环MDSC的频率显着降低，特别是未接受高效抗逆转录病毒治疗（HAART）的患者。这种通常限制有害免疫激活的重要调节群体的缺乏可能会显着导致全身区室和肠粘膜组织中不受控制的慢性炎症，以及在 HIV-1 感染者中观察到的自身免疫性疾病的高发病率。我们将通过三个具体目标来探讨 MDSC 在 HIV-1 感染中的作用： 1）确定 HIV-1 感染者的血液和肠道组织中 MDSC 的频率是否降低； 2）确定MDSC是否可以直接感染HIV-1； 3)确定HIV-1感染患者中的MDSC是否保留其免疫抑制活性。阐明 MDSC 在 HIV-1 感染中的作用可能有助于设计新的治疗策略，该策略基于 MDSC 群体的受控扩张，从而抑制 HIV-1 感染患者的慢性免疫激活。公共健康相关性：在本申请中，我们提出了一项新的观察结果，即 HIV-1 感染与骨髓源性抑制细胞 (MDSC) 的严重耗竭相关，并假设这种重要免疫调节群体的缺失会显着导致慢性免疫激活CD4+T细胞逐渐减少。慢性 T 细胞激活机制的精确表征对于我们理解 HIV-1 发病机制至关重要。阐明 MDSC 在 HIV-1 感染中的作用可能有助于设计新的治疗策略，该策略基于 MDSC 群体的受控扩张，从而抑制 HIV-1 感染患者的慢性免疫激活。