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）：每年感染6个月以下的近400万婴儿死亡，其中许多是可预防疫苗的。婴儿免疫系统不能像老年儿童或成人一样有效地控制感染或对疫苗接种的反应，这归因于免疫学不成熟。在这里，我们确定了一种解释这种降低的年轻婴儿免疫力的机制：它们具有先天调节细胞，称为髓样衍生的抑制细胞（MDSC），它们是NK细胞和T细胞激活的有效抑制剂。 MDSC以前从未在婴儿中描述过，在健康的成年人中很少见。 MDSC最好在成年癌症患者中表征，尽管他们对抗肿瘤T细胞活性具有显着，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种群抑制了婴儿NK和T细胞反应，从而导致对感染和生命早期感染和疫苗接种的效率低下。本应用程序中针对的目的将在表型和功能上定义脐带血中的MDSC。我们将在生命的第一年对婴儿进行纵向研究，以评估MDSC对婴儿免疫反应对常规儿童期疫苗和感染的影响。此外，目的将确定MDSC对新生儿NK和T细胞的抑制是否依赖于使用精氨酸酶-1抑制剂。最后，我们将确定抑制是否 MDSC功能的功能将消除其抑制作用，并增强新生儿NK和T细胞活性。早期疫苗接种的挑战在于婴儿免疫反应的局限性。因此，有必要阐明降低新生儿免疫力背后的机制，以阐明增强婴儿免疫反应的方法。公共卫生相关性：这项研究的总体目标是确定MDSC是否参与了有据可查的婴儿无法应对感染/疫苗接种和对确定可能在临床环境中应用的干预措施。