Naturally Occurring Lipid Mediators Enhance Antibody Production

天然存在的脂质介质增强抗体产生

• 批准号: 8606727
• 负责人: RICHARD P. PHIPPS
• 金额: $ 19.19万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606727
• 关键词: Adjuvant; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Antibodies; Antibody Formation; Antigens; Asthma; B cell differentiation; B-Lymphocytes; Body Weight decreased; CD59 Antigen; Cell physiology; Cells; Chronic; Complement; Data; Disease; Dose; Elderly; Enhancing Antibodies; Enzyme-Linked Immunosorbent Assay; Family; Flow Cytometry; Goals; Health; Hemagglutinin; Homeostasis; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; Infant; Infection; Infectious Agent; Inflammation; Inflammatory; Influenza; Influenza A Virus, H1N1 Subtype; Influenza vaccination; Knowledge; Lead; Life; Ligands; Lipids; Lipoxins; Lung Inflammation; Measures; Mediating; Mediator of activation protein; Memory; Memory B-Lymphocyte; Mitogens; Modeling; Monitor; Mus; Neutrophil Infiltration; Periodontitis; Phase; Phenotype; Polyunsaturated Fatty Acids; Population; Pre-Clinical Model; Process; Property; Recombinant Proteins; Recording of previous events; Regulation; Resolution; Role; T-Lymphocyte; Testing; Universities; Vaccinated; Vaccination; Vaccines; Viral; Virus; adaptive immunity; booster vaccine; cytokine; flu; human subject; immunogenic; improved; influenza virus vaccine; influenzavirus; lipid mediator; long term memory; microorganism; monocyte; pandemic disease; pathogen; patient population; peripheral blood; pre-clinical; prevent; public health relevance; response; seasonal influenza; vaccine efficacy

DESCRIPTION (provided by applicant): An emerging concept is that resolution of inflammation is a dynamic process crucial in restoring homeostasis, thus preventing chronic inflammation and disease. Newly identified lipid mediators, derived from polyunsaturated fatty acids (PUFA) are now recognized as crucial players in resolving inflammation. These endogenous specialized proresolution mediators (SPM) constitute separate families including lipoxins, resolvins, protectins and maresins. SPM have newly discovered abilities to regulate cells of the immune system. The humoral response is essential for protection against microorganisms, however the role of SPM in humoral immunity and their effect on B cells has not yet been studied. This is an important knowledge gap. Our new pilot data in support of this R21 application show that SPM have an important ability to enhance mitogen and antigen-driven antibody responses. These results support our hypothesis that the lipid-derived SPM enhance the antibody response to infection by promoting B cell function, leading to improved immune memory and long-term protection. We propose to study the immuno-regulatory functions of SPM on human and mouse B cells and during the adaptive immune response against influenza, in an infection and vaccination pre-clinical model. Adjuvant or "vaccine booster" properties of SPM could increase vaccine efficacy and utility, permitting smaller doses when a vaccine is poorly immunogenic or in short supply. We propose two specific aims to begin to reveal the function of SPM on B cells. Aim 1: Characterize the ability of key SPM to stimulate human B cell antibody production. B cells will be activated with TLR and BCR ligands along with selected SPM. IgM and IgG antibody levels will be determined along with B cell phenotype, survival and proliferation analyses. We will study B cell memory responses using seasonal influenza-vaccinated human subjects. These studies will determine the effects of resolvins on memory and antibody-secreting B cell populations. Aim 2: Determine the capacity of lead SPM to stimulate protective antibody production in a pre-clinical mouse influenza virus vaccination and infection model. The functions of SPM during an adaptive memory response will be analyzed using a mouse influenza vaccination and infection model. Mice will be vaccinated using the trivalent seasonal flu vaccine, as well as influenza recombinant protein, hemagglutinin (HA), and complemented with or without SPM. IgM and IgG antibody titers will be measured along with the antibodies' inhibitory and neutralizing properties, reflective of a B cell-mediated adaptive response. The stimulatory properties of SPM will be further assessed by challenging immunized mice with live influenza viral strains, including the 2009 H1N1, and monitoring weight loss, survival, and viral titers.

描述（由申请人提供）：一个新兴概念是炎症的消退是一个动态过程，对于恢复体内平衡至关重要，从而预防慢性炎症和疾病。新发现的源自多不饱和脂肪酸（PUFA）的脂质介质现在被认为是解决炎症的关键因素。这些内源性专门的促分解介质 (SPM) 构成了不同的家族，包括脂氧素、分解素、保护素和 maresins。 SPM 具有新发现的调节免疫系统细胞的能力。体液反应对于抵御微生物至关重要，但 SPM 在体液免疫中的作用及其对 B 细胞的影响尚未研究。这是一个重要的知识差距。我们支持 R21 应用的新试验数据表明，SPM 具有增强丝裂原和抗原驱动抗体反应的重要能力。这些结果支持我们的假设，即脂质衍生的 SPM 通过促进 B 细胞功能来增强抗体对感染的反应，从而改善免疫记忆和长期保护。我们建议在感染和疫苗接种临床前模型中研究 SPM 对人类和小鼠 B 细胞以及针对流感的适应性免疫反应期间的免疫调节功能。 SPM 的佐剂或“疫苗加强剂”特性可以提高疫苗的功效和实用性，当疫苗免疫原性较差或供应短缺时，可以使用较小的剂量。我们提出了两个具体目标来开始揭示 SPM 对 B 细胞的功能。目标 1：表征关键 SPM 刺激人类 B 细胞抗体产生的能力。 B 细胞将被 TLR 和 BCR 配体以及选定的 SPM 激活。 IgM 和 IgG 抗体水平将与 B 细胞表型、存活和增殖分析一起确定。我们将使用接种季节性流感疫苗的人类受试者来研究 B 细胞记忆反应。这些研究将确定解析素对记忆和抗体分泌 B 细胞群的影响。目标 2：确定先导 SPM 在临床前小鼠流感病毒疫苗接种和感染模型中刺激保护性抗体产生的能力。将使用小鼠流感疫苗接种和感染模型来分析 SPM 在适应性记忆反应期间的功能。小鼠将使用三价季节性流感疫苗以及流感重组蛋白、血凝素 (HA) 进行疫苗接种，并补充或不补充 SPM。 IgM 和 IgG 抗体滴度将与抗体的抑制和中和特性一起测量，反映 B 细胞介导的适应性反应。 SPM 的刺激特性将通过用活流感病毒株（包括 2009 H1N1）攻击免疫小鼠并监测体重减轻、存活和病毒滴度来进一步评估。