Innate Immunity to Influenza in Caloric Restricted Aged Mice

热量限制老年小鼠对流感的先天免疫

• 批准号: 7304493
• 负责人: Elizabeth M. Gardner
• 金额: $ 18.45万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7304493
• 关键词: Age; Antibodies; Antibody Formation; Antigens; Body Weight; Body Weight decreased; C57BL/6 Mouse; CCL2 gene; CD8B1 gene; Caloric Restriction; Cause of Death; Cell Count; Cessation of life; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Defect; Dendritic Cells; Development; Diet; Elderly; Event; Exhibits; Granzyme; Histology; Immune; Immune response; Immunity; Impairment; In Vitro; Incidence; Infection; Influenza; Interferons; Interleukin-1; Interleukin-12; Interleukin-15; Interleukin-18; Interleukin-6; Investigation; Life; Longevity; Lung; Lymphocyte; Macrophage Inflammatory Protein-1; Maintenance; Malignant Neoplasms; Malnutrition; Mediastinal lymph node group; Mitogens; Mus; NK Cell Activation; Natural Immunity; Natural Killer Cells; Numbers; Outcome; Pathology; Persons; Pneumonia; Predisposition; Principal Investigator; Production; Recovery; Relative (related person); Reporting; Research; Rodent; Secondary to; Signal Transduction; Small Inducible Cytokine A3; T-Cell Proliferation; T-Lymphocyte; TNF gene; Time; United States; Virus; Virus Diseases; Weight; age related; aged; base; cell type; chemokine; cytokine; cytotoxicity; day; feeding; human old age (65+); immune function; influenza virus vaccine; influenzavirus; macrophage; mouse model; perforin; programs; research study; response; tumor

DESCRIPTION (provided by applicant): Influenza and its secondary pneumonias are the fourth leading cause of death in persons 65 years and older in the United States. Caloric restriction (CR) extends median and maximal life span in healthy rodents, compared to those fed ad-libitum (AL). Aged CR rodents show decreases in tumors and cancers, and increases in antibody titers and T cell proliferation suggesting CR delays the onset of age-related decreased immune function. We have employed a mouse model of CR to examine the age-related decline in primary response to influenza. Although CR delayed the age-related decline in T cell proliferation, in stark contrast, aged CR mice died 4-6 days after primary influenza infection, exhibiting increased lung virus titers and reduced pulmonary NK activity. Importantly, CR mice weighed 30% less than AL mice at the time of infection and had dramatic weight loss following infection. Due to the early time course, we hypothesize that aged CR mice cannot control primary influenza infection because of altered innate immunity. This may reflect an intrinsic defect in NK cells themselves or may be secondary to an extrinsic defect involving signals produced early on by macrophages and/or dendritic cells. Specifically, we will: 1) Determine if enhanced susceptibility of CR mice to primary influenza infection is age-dependent. Young AL and CR C57BL/6 mice will be infected with influenza and survival, weight loss and recovery, cell types in lung and mediastinal lymph nodes, and lung virus titers will be evaluated. 2) Investigate mechanism(s) for reduced NK activity during primary influenza infection. We will assess NK function by cytotoxicity, perforin and granzyme production, in vitro stimulation of NK cells with IFN-a/¿, and cytokine production. We will investigate whether decreased NK cell activity is related to decreased NK cell number or NK cells as a percentage of total lymphocytes in lung. We will further determine if the defect in NK number or function results from impaired recruitment and/or activation of NK cells by cytokines produced by macrophages/dendritic cells. We will quantitate activation markers on macrophage and dendritic cells in lung and their cytokine and chemokine production (IFN-a/¿?, IL-12, IL-15, IL-18, MIP-1a/¿, MCP-1, IL-1¿, IL-6, TNF-a). 3) Determine if the susceptibility of CR mice to influenza is related to reduced body weight and if refeeding prior to infection restores the immune response to influenza infection. CR mice will be fed AL diets to restore weight to 50% and 100% of AL mice before infection with influenza and outcomes in Specific Aims 1 and 2 will be assessed.

描述（由适用提供）：流感及其次要肺炎是美国65岁及以上的人的第四大死亡原因。与饲养的脂肪（AL）相比，热量限制（CR）在健康啮齿动物中延伸了中位数和最大寿命。老化的CR啮齿动物在肿瘤和癌症中显示出下降，抗体滴度和T细胞增殖的增加表明CR延迟了与年龄相关的降低免疫功能的发作。我们采用了CR的小鼠模型来检查主要反应对影响的年龄相关的下降。尽管CR延迟了T细胞增殖与年龄相关的下降，但在鲜明的对比中，年龄的CR小鼠在原发性影响病毒感染后4-6天死亡，表现出增加的肺病毒滴度和肺NK活性降低。重要的是，在感染时，CR小鼠的重量比AL小鼠少30％，并且感染后体重减轻。由于早期过程，我们假设老化的Cr小鼠无法控制先天免疫的原发性影响。这可能反映了NK细胞本身的固有缺陷，或者可能是涉及巨噬细胞和/或树突状细胞早期产生的信号的外部缺陷。具体而言，我们将：1）确定CR小鼠对主要影响的敏感性是否增强。年轻的AL和CR C57BL/6小鼠将感染影响力和生存，体重减轻和恢复，肺和纵隔淋巴结中的细胞类型，以及将评估肺病毒滴度。 2）研究原发性影响力感染期间NK活性降低的机制。我们将通过细胞毒性，穿孔蛋白和颗粒酶产生，用IFN-A/¿的NK细胞以及细胞因子产生来评估NK功能。我们将研究NK细胞活性的降低是否与NK细胞数量降低或NK细胞有关，占肺总淋巴细胞的百分比。我们将进一步确定NK数量或功能中的缺陷是否是由于巨噬细胞/树突状细胞产生的细胞因子对NK细胞的募集受损和/或激活而导致的。 （IFN-A/¿ 3）确定CR小鼠影响的敏感性是否与体重的减轻有关，以及在感染之前引用是否会恢复影响感染的免疫激发。将评估CR小鼠在感染前的影响和结果1和2中的结果之前，将饮食喂养，以将重量恢复到50％和100％的Al小鼠。

项目成果

NK cell maturation and function in C57BL/6 mice are altered by caloric restriction.

• DOI: 10.4049/jimmunol.1201837
• 发表时间: 2013-01-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Clinthorne JF;Beli E;Duriancik DM;Gardner EM
• 通讯作者: Gardner EM

Differential effects of stimulatory factors on natural killer cell activities of young and aged mice.

• DOI: 10.1093/gerona/gls079
• 发表时间: 2012-09
• 期刊: The journals of gerontology. Series A, Biological sciences and medical sciences
• 作者: Shoko Nogusa;D. Murasko;E. Gardner