Retinoid Nutritional Status and Immune Function

类维生素A营养状况和免疫功能

• 批准号: 8013381
• 负责人: A. CATHARINE ROSS
• 金额: $ 9.41万
• 依托单位: PENNSYLVANIA STATE UNIVERSITY, THE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-19 至 2012-02-18
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8013381
• 关键词: Adult; Affect; All-Trans-Retinol; Animal Model; Anti-Infective Agents; Antibodies; Antibody Formation; Antibody-Producing Cells; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Biochemical; CD38 molecule; CD4 Positive T Lymphocytes; Cell Differentiation process; Cell Maturation; Cell physiology; Cell surface; Cells; Child; Communicable Diseases; Competence; Confocal Microscopy; Dendritic Cells; Disease; Down-Regulation; Equilibrium; Family member; Flow Cytometry; Glycolipids; Goals; Grant; Helper-Inducer T-Lymphocyte; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunization; Immunoassay; Immunocompromised Host; Individual; Infant; Interleukin-4; Life; Ligands; Lymphocyte Activation; Measles; Memory; Microscopic; Modeling; Molecular Analysis; Morbidity - disease rate; Mucosal Immunity; Mus; Neonatal; Nutritional; Nutritional status; Outcome; Plasma; Plasma Cells; Play; Poly I-C; Pregnant Women; Prevention; Production; RNA Editing; Reaction; Regulation; Research; Research Personnel; Retinoids; Role; Signal Transduction; Spleen; Staging; Stimulus; Structure of germinal center of lymph node; T-Lymphocyte; TLR3 gene; Techniques; Testing; Tetanus Toxoid; Thymus Gland; Time; Toll-like receptors; Tretinoin; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Up-Regulation; Vaccination; Vitamin A; Vitamin A Deficiency; Vitamins; Work; activation-induced cytidine deaminase; adaptive immunity; aged; base; clinically relevant; cytokine; human TLR3 protein; immune function; in vivo; killer T cell; mortality; named group; neonate; programs; receptor; transcription factor

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.

描述（由申请人提供）：维生素 A 及其活性代谢物视黄酸 (RA) 以多种方式影响免疫系统。我们的研究重点是类维生素A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力。最近，我们利用小鼠证明，RA 和细胞因子诱导剂 Poly-l:C (PIC) 的营养免疫组合可以共同作用，在成年和新生小鼠中刺激更强的初级和记忆抗体反应。我们的长期目标是了解 RA 和共刺激如何增强抗原特异性抗体反应，特别是对于幼儿和因维生素 A 缺乏或疾病而削弱免疫系统的个体。该提案的中心假设是“视黄酸是 VA 的活性代谢物，与免疫共刺激——尤其是 Toll 样受体 (TLR)-3​​ 配体、poly-l:C (PIC)、信号共受体 CD38 和肿瘤坏死因子家族成员——协同作用，显着调节新生儿和成人阶段的抗体产生。”我们将结合使用细胞和分子分析、流式细胞术、共聚焦显微镜和免疫分析来更好地了解 RA 和共刺激如何促进 B 细胞的激活以及体内抗体对免疫的反应。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中分离出的 B 细胞； 2) 确定 RA 和共刺激如何调节生发中心 (GC) 的形成，生发中心是产生抗体的细胞成熟的特殊微环境； 3) 测试称为 iNKT 细胞的特殊 T 细胞群是否对 RA 加共刺激有反应，以及联合营养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：疫苗接种是婴儿和儿童的一种挽救生命的策略。维生素 A 的活性代谢物视黄酸与内源性和外源性免疫刺激物一起，可能是促进 B 淋巴细胞活化和体内产生强烈、持久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 的营养免疫组合加上免疫刺激的几种免疫刺激是否可以促进 B 细胞活化，诱导产生强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。