Retinoid Nutritional Status and Immune Function

描述(申请人提供)：维生素A及其活性代谢物维甲酸(RA)以多种方式影响免疫系统。我们的研究重点是维甲酸与内源性和外源性共刺激分子共同作用的能力，以促进成人和新生儿强大而持久的免疫。在小鼠身上，我们最近证明了RA和细胞因子诱导剂聚L：C(PIC)的营养免疫学组合可以共同作用，在成年和新生小鼠中激发更强的初级和记忆抗体反应。我们的长期目标是了解RA和协同刺激如何增强抗原特异性抗体反应，特别是在非常年轻的人和免疫系统因维生素A缺乏或疾病而减弱的人中。这项建议的中心假设是“维甲酸，一种VA的活性代谢物，与免疫协同刺激--特别是TLR3配体、多聚L：C(PIC)、信号辅助受体CD38和肿瘤坏死因子家族成员--合作，显著调节新生儿和成年阶段抗体的产生。”我们将结合细胞和分子分析、流式细胞术、共聚焦显微镜和免疫分析来更好地了解RA和协同刺激如何促进B细胞的激活和体内对免疫的抗体反应。我们的3个目标是：1)确定RA和共刺激分子如何激活从成年和新生小鼠分离的B细胞；2)确定RA和共刺激如何调节生发中心(GC)的形成，生发中心(GC)是产生抗体的细胞成熟的专门微环境；3)测试一种特殊的T细胞，称为iNKT细胞，对RA加共刺激是否有反应，以及联合营养和免疫治疗是否可以平衡最佳免疫反应所需的细胞因子的产生。相关性：接种疫苗是婴儿和儿童的一种挽救生命的策略。维生素A的活性代谢物维甲酸与内源性和外源性免疫刺激一起，可能是促进B淋巴细胞激活和体内产生强大、持久的抗体反应的有效组合，这是预防传染病所必需的。我们的研究将使用生化和显微技术来测试RA和几种免疫刺激的营养免疫学组合是否可以促进B细胞的激活，诱导产生强大抗体所需的微结构变化，并提高成年和新生小鼠的血浆抗体水平。

DESCRIPTION (provided by applicant): Vitamin A and its active metabolite, retinoic acid (RA), affect the immune system in multiple ways. Our research is focused on the ability of retinoids to work together with co-stimulatory molecules, of both endogenous and exogenous origin, to promote strong and long-lasting immunity in adults and neonates. Using mice, we have recently shown that a nutritional-immunological combination of RA and a cytokine inducer, poly-l:C (PIC), can act together to stimulate much stronger primary and memory antibody responses in both adult and neonatal mice. Our long-term goal is to understand how RA and co-stimuli can augment antigen-specific antibody responses, especially in the very young and in individuals whose immune system is weakened by vitamin A deficiency or disease. The central hypothesis of this proposal is "Retinoic acid, an active metabolite of VA, cooperates with immunological co-stimuli - especially the Toll-like Receptor (TLR)-3 ligand, poly-l:C (PIC), the signaling co-receptor CD38, and tumor necrosis factor family members - to significantly regulate antibody production at both the neonatal and adult stages of life." We will use a combination of cell and molecular analysis, flow cytometry, confocal microscopy, and immunoassays to better understand how RA and co-stimuli promote the activation of B-cells and the antibody response to immunization in vivo. Our 3 aims are: 1) To determine how RA and costimulatory molecules activate B cells isolated from adult and neonatal mice; 2) To establish how RA and co-stimulation regulate the formation of germinal centers (GC), a specialized microenvironment where antibody-producing cells mature; 3) To test whether a special population of T-cells, referred to as iNKT cells, are responsive to RA plus costimuli, and whether a combined nutritional-immunological treatment can balance the production of cytokines that are needed for an optimal immune response. Relevance: Vaccination is a life-saving strategy for infants and children. Vitamin A's active metabolite, retinoic acid, together with immune stimuli of endogenous and exogenous origin, may be an effective combination for promoting B-lymphocyte activation and the production of a strong, durable antibody response in vivo, as is necessary for protection against infectious disease. Our studies will use biochemical and microscopic techniques to test whether nutritional-immunological combinations of RA plus several immune stimuli, given with immunization, can promote B-cell activation, induce microarchitectural changes needed for strong antibody production, and increase the plasma antibody levels in adult and neonatal mice.