Myeloid-derived Suppressor cells (MDSC) suppress infant immune responses

骨髓源性抑制细胞 (MDSC) 抑制婴儿免疫反应

基本信息

批准号：
8298408
负责人：
HELEN HORTON
金额：
$ 47.48万
依托单位：
SEATTLE BIOMEDICAL RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8298408
关键词：
Address Adult Africa South of the Sahara Age-Months Antibodies Antibody Formation Antigen-Presenting Cells Area Automobile Driving Biological Assay Birth Blood Cancer Patient Cell physiology Cells Child Childhood Clinical Country Cytomegalovirus Developed Countries Developing Countries Disease Drug usage Ensure Fetus Flow Cytometry Frequencies Goals Growth Herpesvirus 1 Human Immune Immune Cell Suppression Immune response Immune system Immunity Immunologics In Vitro Individual Infant Infant Mortality Infection Infection Control Intervention Lead Life Live Birth Longitudinal Studies Measures Myelogenous Natural Killer Cells Neonatal Newborn Infant Oropharyngeal Peripheral Blood Mononuclear Cell Phenotype Plasma Population Pregnancy Prevalence Recruitment Activity Relative (related person)Resources Retinoids Role Sampling Simplexvirus Site South Africa Suppressor-Effector T-Lymphocytes Swab T cell response T-Cell Activation T-Lymphocyte Testing Time Uganda Umbilical Cord Blood Vaccination Vaccines Viral Virus Virus Diseases Vitamin A Vulnerable Populations Work arginase cohort early childhood fetal global health immune activation inhibitor/antagonist killer T cell mortality neonate peripheral blood response sildenafil small molecule therapy development tumor

项目摘要

DESCRIPTION (provided by applicant): Almost 4 million infants under 6 months old die each year of infections, many of which are vaccine-preventable. The infant immune system cannot control infection, or respond to vaccination, as effectively as older children's or adults', which has been attributed to immunologic immaturity. Here, we have identified a mechanism to explain this reduced immunity in young infants: they possess innate regulatory cells, called myeloid-derived suppressor cells (MDSC), which are potent inhibitors of both NK cell and T cell activation. MDSC have never been described before in infants, and are rarely seen in healthy adults. MDSC have best been characterized in adult cancer patients where they have remarkable, albeit reversible, suppressive effects on anti-tumor T cell activity. Our overall hypothesis is that MDSC populations present in neonates and infants suppress infant NK and T cell responses resulting in inefficient responses to both infection and vaccination early in life. The aims addressed in this application will phenotypically and functionally define MDSC in cord blood. We will perform longitudinal studies in infants during the first year of life to assess the influence of MDSC on infant immune responses to routine childhood vaccines and infections. In addition, the aims will determine if suppression of neonatal NK and T cells by MDSC is arginase-1-dependent with the use of arginase-1 inhibitors. Finally we will determine if inhibition of MDSC function will abrogate their suppressive actions and enhance neonatal NK and T cell activity. The challenge of early life vaccination lies in the limitations of the infant immune response. Thus, it is pertinent to elucidate the mechanisms behind reduced neonatal immunity to illuminate ways to enhance infant immune responses. PUBLIC HEALTH RELEVANCE: The overarching goal of this study is to determine if MDSC are involved in the well-documented inability of infants to respond to infection/vaccination and to identify possible interventions that could be applied in a clinical setting.

描述（由申请人提供）：每年有近 400 万 6 个月以下的婴儿死于感染，其中许多是可以通过疫苗预防的。婴儿免疫系统无法像年龄较大的儿童或成人那样有效地控制感染或对疫苗接种做出反应，这归因于免疫不成熟。在这里，我们发现了一种机制来解释年幼婴儿免疫力下降的情况：他们拥有先天调节细胞，称为骨髓源性抑制细胞 (MDSC)，它们是 NK 细胞和 T 细胞激活的有效抑制剂。以前从未在婴儿中描述过 MDSC，并且在健康成人中也很少见到。 MDSC 在成年癌症患者中得到了最好的表征，它们对抗肿瘤 T 细胞活性具有显着但可逆的抑制作用。我们的总体假设是，新生儿和婴儿中存在的 MDSC 群体抑制婴儿 NK 和 T 细胞反应，导致生命早期对感染和疫苗接种的反应低效。本申请的目标将从表型和功能上定义脐带血中的 MDSC。我们将对出生后第一年的婴儿进行纵向研究，以评估 MDSC 对婴儿对常规儿童疫苗和感染的免疫反应的影响。此外，目的是确定使用精氨酸酶 1 抑制剂时 MDSC 对新生儿 NK 和 T 细胞的抑制是否依赖于精氨酸酶 1。最后我们将确定是否抑制 MDSC 功能的减弱将消除其抑制作用并增强新生儿 NK 和 T 细胞活性。生命早期疫苗接种的挑战在于婴儿免疫反应的局限性。因此，有必要阐明新生儿免疫力下降的机制，以阐明增强婴儿免疫反应的方法。公共卫生相关性：本研究的首要目标是确定 MDSC 是否与有充分记录的婴儿对感染/疫苗和接种无反应能力有关。确定可应用于临床环境的可能干预措施。