Cellular expression and regulation of interleukin-27 in the neonatal immune syste

新生儿免疫系统中白细胞介素27的细胞表达和调节

• 批准号: 8890783
• 负责人: Cory Michael Robinson
• 金额: $ 7.15万
• 依托单位: WEST VIRGINIA SCHOOL OF OSTEOPATHIC MED
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-07-15 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8890783
• 关键词: Address; Adult; Antigen-Presenting Cells; Bacterial Infections; Cells; Chemicals; DNA Methylation; DNA Methyltransferase Inhibitor; DNA Sequence; Data; Enzymes; Epigenetic Process; Exhibits; Family; Gene Expression; Histones; Human; Immune; Immune response; Immune system; Immunosuppressive Agents; Infant; Infant Mortality; Infection; Infectious Agent; Inflammation; Interferon Type II; Interleukin-12; Interleukins; Investigation; Knowledge; Laboratories; Life; Molecular; Mus; Mycobacterium tuberculosis; Myelogenous; Nature; Neonatal; Newborn Infant; Nucleosomes; Phenotype; Population; Predisposition; Production; Quantitative Evaluations; Regulation; Research; Signal Transduction; Splenocyte; Staging; Suppressor-Effector T-Lymphocytes; System; T cell response; T-Lymphocyte; Testing; TimeLine; Umbilical Cord Blood; Vaccination; Virus Diseases; adaptive immunity; age related; cell type; cytokine; differential expression; epigenetic regulation; histone modification; improved; infancy; macrophage; microbial; monocyte; mouse development; mouse model; neonate; pathogen; public health relevance; response

DESCRIPTION (provided by applicant): Microbial infections are a major cause of infant mortality worldwide as a result of impaired immune defenses in this population. We have found that human umbilical cord blood-derived macrophages express interleukin (IL) - 27 at an elevated level as compared with healthy adult macrophages. We have further determined that elevated IL-27 production by newborns is maintained through infancy in a mouse model. IL-27 is a heterodimeric cytokine of the IL-12 family that is produced primarily by antigen presenting cells and is immunosuppressive toward a variety of immune cell types. Thus, elevated IL-27 expression early in life may contribute to some of the deficiencies described with immune responses by this population. The nature of this proposal is to understand the complete repertoire of cell types that contribute to elevated IL-27 production in neonates and infants as well as to further understand the molecular mechanisms responsible for differential expression. In the first aim, we will evaluate the cellular phenotypes of cells that produce IL-27 with a particular focus toward myeloid-derived suppressor cells. These cells have potent ability to suppressive inflammation and adaptive immunity. The second aim tests the hypothesis that IL-27 is regulated by epigenetic mechanisms that contribute to differences in age-related expression. This will focus on DNA methylation and nucleosome remodeling through histone modification. We have proposed research that investigates the impact of IL-27 on neonatal immune responses. Approaches to reduce expression of IL-27 in newborns and infants may improve vaccination responses and reduce susceptibility to infectious agents.

描述（由申请人提供）：微生物感染是全球婴儿死亡的主要原因，这是由于该人群免疫防御受损的结果。我们发现，与健康成人巨噬细胞相比，人脐带血源性巨噬细胞表达白细胞介素(IL) - 27的水平升高。我们进一步确定，在小鼠模型中，新生儿IL-27的升高在婴儿期保持。IL-27是IL-12家族的一种异二聚体细胞因子，主要由抗原呈递细胞产生，对多种免疫细胞类型具有免疫抑制作用。因此，生命早期IL-27表达的升高可能会导致该人群免疫反应中描述的一些缺陷。这一建议的本质是了解促成新生儿和婴儿IL-27产生升高的细胞类型的完整库，以及进一步了解负责差异表达的分子机制。在第一个目标中，我们将评估产生IL-27的细胞的细胞表型，特别关注髓源性抑制细胞。这些细胞具有抑制炎症和适应性免疫的强大能力。第二个目的是测试IL-27受表观遗传机制调控的假设，这种机制导致了年龄相关表达的差异。这将集中在DNA甲基化和核小体重塑通过组蛋白修饰。我们建议研究IL-27对新生儿免疫反应的影响。降低新生儿和婴儿IL-27表达的方法可能改善疫苗接种反应并降低对传染性病原体的易感性。