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（由申请人提供）：流感及其继发性肺炎是美国 65 岁及以上人群的第四大死亡原因，与喂食广告的啮齿类动物相比，热量限制 (CR) 延长了健康啮齿类动物的中位寿命和最大寿命。老年CR啮齿动物的肿瘤和癌症有所减少，抗体滴度和T细胞增殖增加，表明CR延迟了与年龄相关的免疫功能下降的发生。 CR 检查与年龄相关的流感原发反应下降虽然 CR 延迟了与年龄相关的 T 细胞增殖下降，但与此形成鲜明对比的是，老年 CR 小鼠在原发性流感感染后 4-6 天死亡，表现出肺部病毒滴度增加和重要的是，CR 小鼠在感染时体重比 AL 小鼠轻 30%，并且在感染后体重急剧下降，我们发现老年 CR 小鼠由于先天性而无法控制原发性流感感染。这可能反映了内在的缺陷。具体而言，我们将： 1) 确定 CR 小鼠对原发性流感感染的易感性是否与年龄有关。 CR C57BL/6 小鼠将感染流感，并评估存活率、体重减轻和恢复、肺和纵隔淋巴结中的细胞类型以及肺病毒滴度 2) 研究以下机制。原发性流感感染期间 NK 活性降低 我们将通过细胞毒性、穿孔素和颗粒酶的产生、用 IFN-a/¿ 体外刺激 NK 细胞来评估 NK 功能。我们将研究 NK 细胞活性下降是否与 NK 细胞数量或 NK 细胞占肺中淋巴细胞总数的百分比下降有关。我们将进一步确定 NK 数量或功能的缺陷是否是由于招募和/或受损所致。或巨噬细胞/树突状细胞产生的细胞因子激活 NK 细胞 我们将定量肺中巨噬细胞和树突状细胞的激活标记及其细胞因子和趋化因子的产生（IFN-a/??， 3) 确定 CR 小鼠对流感的易感性是否与体重减轻有关，感染前重新喂养是否可以恢复对流感感染的免疫反应，将给 CR 小鼠喂食 AL 饮食，使体重恢复到 AL 小鼠的 50% 和 100%。感染流感之前和结果将评估具体目标 1 和 2。

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