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

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，因为该人群的免疫防御受损。我们已经发现，人脐带血来源的巨噬细胞表达白细胞介素（IL）-27在一个升高的水平相比，健康的成年巨噬细胞。我们进一步确定，在小鼠模型中，新生儿产生的IL-27升高一直维持到婴儿期。IL-27是IL-12家族的异二聚体细胞因子，其主要由抗原呈递细胞产生，并且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表达升高可能导致该人群免疫应答中的一些缺陷。该提案的本质是了解有助于新生儿和婴儿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。这些细胞具有强大的抑制炎症和适应性免疫的能力。第二个目的是检验IL-27受表观遗传机制调节的假设，表观遗传机制导致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。我们已经提出了研究IL-27对新生儿免疫应答的影响的研究。降低新生儿和婴儿中IL-27表达的方法可能会改善疫苗接种反应并降低对感染因子的易感性。

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.