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）：髓样衍生的抑制细胞（MDSC）是最近表征的细胞群，在癌症，感染，炎症和创伤期间扩展。 MDSC表现出通过多种机制抑制T细胞介导的免疫力的显着能力，包括精氨酸酶1的产生，活性氧，一氧化氮以及调节性T细胞的诱导。 MDSC代表了一种重要的调节反馈免疫机制，可防止各种疾病中夸张的慢性炎症。 HIV-1感染的特征是CD4+和CD8+ T细胞的慢性激活和快速周转。最近获得的证据表明，HIV-1感染与胃肠道粘膜组织中的慢性炎症有关，以及将微生物产物转移到系统室中，它们会导致T细胞激活。 CD4+ T细胞再生能力的激活驱动的耗竭最终导致CD4+ T细胞稳态的崩溃。慢性T细胞激活的机制的精确表征对于理解HIV-1发病机理至关重要。可以预期，与HIV-1感染相关的慢性免疫激活将导致MDSC种群显着扩大，如其他病毒和细菌感染中所观察到的。令人惊讶的是，我们的初步数据表明，HIV-1感染的患者循环MDSC的频率显着降低，尤其是未接受高度活性抗网状病毒治疗（HAART）治疗的患者。通常限制有害免疫激活的重要调节群体可能会显着导致全身室和肠粘膜组织中不受控制的慢性炎症，以及在HIV-1感染的个体中观察到的自身免疫性疾病的高发生率。我们将解决MDSC在HIV-1感染中的作用：1）确定HIV-1感染个体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感染中的作用可能在基于MDSC群体的受控扩张的新型治疗策略中发挥作用，从而抑制了HIV-1感染的患者的慢性免疫激活。公共卫生相关性：在本应用中，我们提出了一种新的观察结果，即HIV-1感染与髓样衍生的抑制细胞（MDSC）的严重消耗有关，并假设缺乏这种重要的免疫调节群显着导致CD4+ T细胞逐渐下降的慢性免疫活化。慢性T细胞激活的机制的精确表征对于我们对HIV-1发病机理的理解至关重要。阐明MDSC在HIV-1感染中的作用可能在基于MDSC群体的受控扩张的新型治疗策略中发挥作用，从而抑制了HIV-1感染的患者的慢性免疫激活。