Elizabeth M Gardner
Michigan State University
Project start date: 2010-09-15
Project end date: 2015-06-30
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Elizabeth M Gardner
INNATE IMMUNITY TO INFLUENZA IN CALORIC RESTRICTED AGED MICE
Elizabeth M Gardner, Assistant Professor
Drexel University, Office Of Research, Philadelphia, Pa 19104
Abstract: 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
Keywords: 65+ years old; ATGN; Age; Aged 65 and Over; Antibodies; Antibody Formation; Antibody Production; Antibody Response; Antigens; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Body Weight; Body Weight decreased; C57BL/6 Mouse; CCL2; CCL2 gene; CD8; CD8B; CD8B1; CD8B1 gene; CTL; Caloric Restriction; Cancers; Cause of Death; Cell Communication and Signaling; Cell Count; Cell Number; Cell Signaling; Cell-Mediated Lympholytic Cells; Cessation of life; Chemokine (C-C motif) Ligand 3; Communicable Diseases; Cytokines, Chemotactic; Cytolytic T-Cell; Cytotoxic T Cell; Cytotoxic T-Lymphocytes; Cytotoxic cell; DIF; Data; Death; Defect; Dendritic Cells; Development; Diet; Differentiation Factor, B-Cell; Edodekin Alfa; Elderly; Elderly, over 65; Event; Exhibits; Flu vaccine; GDCF-2; GDCF-2 HC11; Granzyme; Grippe; HC11; HPGF; Hepatocyte-Stimulating Factor; Histology; Homologous Chemotactic Cytokines; Hybridoma Growth Factor; IFN; IFN-beta 2; IFN-gamma-Inducing Factor; IFNB2; IGIF; IL-1; IL-1 Gamma; IL-12; IL-15; IL-18; IL-1g; IL-6; IL1; IL12; IL15; IL15 Protein; IL18 Protein; IL1F4; IL6 Protein; Immune; Immune Function, Cellular; Immune response; Immunity; Immunity, Innate; Immunity, Native; Immunity, Natural; Immunity, Non-Specific; Impairment; In Vitro; Incidence; Infection; Infectious Disease Pathway; Infectious Diseases; Infectious Diseases and Manifestations; Infectious Disorder; Influenza; Influenza Vaccines; Influenza Virus; Influenza virus vaccine; Intercrines; Interferon-gamma-Inducing Factor; Interferons; Interleukin 18 (Interferon-Gamma-Inducing Factor); Interleukin 18 Proprotein; Interleukin 6 (Interferon, Beta 2); Interleukin I; Interleukin-1; Interleukin-1 Gamma; Interleukin-12; Interleukin-15; Interleukin-15 Precursor; Interleukin-18; Interleukin-18 Precursor; Interleukin-6; Intracellular Communication and Signaling; Investigation; K lymphocyte; LYT3; Length of Life; Life; Longevity; Lung; Lymphocyte; Lymphocyte-Stimulating Hormone; Lymphocytic; Lytotoxicity; MCAF; MCP-1; MCP1; MGC12320; MGC9434; MGC9721; MGI-2; MIP 1alpha; MIP-1; MIP-1 Alpha; MIP-1a; MTGN; Macrophage Cell Factor; Macrophage Inflammatory Protein-1; Maintenance; Maintenances; Malignant Neoplasms; Malignant Tumor; Malnutrition; Mammals, Mice; Mammals, Rodents; Mediastinal Lymph Node; Mediastinal lymph node group; Mice; Mitogens; Murine; Mus; Myeloid Differentiation-Inducing Protein; NK Cell Activation; NK Cells; NKSF; Natural Immunity; Natural Killer Cell Activation; Natural Killer Cell Stimulatory Factor; Natural Killer Cells; Numbers; Nutritional Deficiency; Outcome; Pathology; Persons; Plasmacytoma Growth Factor; Pneumonia; Pneumonitis; Predisposition; Principal Investigator; Production; Programs (PT); Programs [Publication Type]; Pulmonary Inflammation; Recovery; Relative; Relative (related person); Reporting; Research; Respiratory System, Lung; Rodent; Rodentia; Rodentias; SCYA2; SIS cytokines; SMC-CF; Secondary to; Signal Transduction; Signal Transduction Systems; Signaling; Small Inducible Cytokine A3; Stem Cell Inhibitor; Susceptibility; T Helper Factor; T-Cell Proliferation; T-Cells; T-Lymphocyte; T-Lymphocytes, Cytotoxic; TNF; TNF A; TNF gene; TNFSF2; Thymus-Dependent Lymphocytes; Time; Tumor Necrosis Factor Gene; Undernutrition; United States; Veiled Cells; Viral Diseases; Virus; Virus Diseases; Viruses, General; Weight; Weight Loss; Weight Reduction; advanced age; age dependent; age related; aged; antibody biosynthesis; base; biological signal transduction; body weight loss; calorie restriction; cell type; chemoattractant cytokine; chemokine; cytokine; cytolysin; cytotoxicity; day; dietary deficiency; elders; experiment; experimental research; experimental study; feeding; flu infection; geriatric; host response; human old age (65+); immune function; immunogen; immunoglobulin biosynthesis; immunoresponse; influenza infection; influenzavirus; influenzavirus (unspecified); interferon beta 2; late life; later life; life span; lifespan; lymph cell; lymphocyte activating factor; lymphocyte pore-forming protein; macrophage; malignancy; mouse model; neoplasm/cancer; older adult; older person; perforin; programs; pulmonary; research study; response; senior citizen; thymus derived lymphocyte; tumor; viral infection; virus infection; wt-loss
Project start date: 2007-09-15
Project end date: 2010-08-31
Budget start date: 15-SEP-2007
Budget end date: 31-AUG-2010
PFA/PA: PA-06-042
1R15AG029637-01A1 (2007): $0
NATURAL KILLER CELL RESPONSES OF AGED MICE TO PRIMARY INFLUENZA INFECTION
Elizabeth M Gardner
Michigan State University, 301 Administration Bldg, East Lansing, Mi 48824
Grant 1R01AG034949-01A1 from National Institute On Aging
Abstract: Despite vaccination, influenza and secondary pneumonias are the fourth leading cause of death in individuals 65 years and older. The recent emergence of the novel 2009-H1N1 influenza, to which vaccines are limited or unavailable, has the potential to cause 30,000-90,000 deaths in people under 65 years of age. These staggering statistics mandate the need to better understand age-related changes in primary immune responses to acute influenza infection. We have recently identified a critical role for natural killer (NK) cells in controlling early influenza infection ex vivo and in vivo. Aged C57BL/6 mice exhibited increased lung virus titers, weight loss, decreased NK cytotoxicity, and a reduced number of NK cells during early influenza infection. Importantly, in vivo NK cell depletion by anti-NK1.1 IgG antibody (PK136) treatment induced marked weight loss and increased lung virus titers after influenza infection of both young and aged mice. These data suggest that NK cells are essential in early control of influenza infection. Thus, our overarching hypothesis is that the induction of an effective NK cell response is vital for controlling early influenza infection in vulnerable populations, including the elderly. Our studies will characterize age-related changes in NK cell function, elucidate potential intrinsic and extrinsic mechanisms for impaired NK cell function, and establish the critical role of NK cells in controlling early infection to influenza virus in vivo. In Aim 1, age-related differences in susceptibility and the role of NK cell function during the first critical four days of infection will be assessed. We will perform influenza dose responses and measure age-related differences lung virus titers, pathology, histology and cellular infiltrates in lung, weight loss, and recovery from infection. Age-related changes in NK subsets, cytolytic function of NK cells, dendritic cell (DCs) function, and local and systemic cytokine production will be measured during infection. In Aim 2, we will elucidate age-related changes in intrinsic and extrinsic mechanism(s) for impaired NK cell function during influenza infection. Age-related differences in lytic efficiency, activation receptor function/signaling, and cytokine receptor/function will be measured in purified NK cells to identify intrinsic NK cell defects. Adoptive transfer studies will delineate between intrinsic and extrinsic effects on NK cell proliferation, apoptosis, and homing as related to susceptibility to influenza. We hypothesize that DCs are critical extrinsic effectors on NK cell function in early infection. Thus, we will measure DC activation of NK cells, DC cytokine production, and the effects of DC ablation on NK cell function. In Aim 3, we will validate the essential role of NK cells in controlling the in vivo response to influenza. In vivo NK cytolysis in young and aged mice will be assessed along with survival, weight loss, and lung virus titers. The specific role of NK cells in controlling susceptibility to influenza will be addressed in mice after NK depletion in vivo with PK136 or in RAG-1-/- or NKD transgenic mice. These three mouse models will afford a clear delineation of the specific contribution of NK cells in controlling the early response to influenza. The prevalence of seasonal influenza and the recent emergence of swine 2009-H1N1 mandate the need to study age-related changes in the primary response to influenza infection. Aged mice show decreased NK cell function and elevated lung virus titers during the first four days of infection, and more importantly, die prior the initiation of an adaptive primary response. If applicable to humans, this suggests that the ability of young and aged individuals to mount an early and effective NK cell response to influenza infection is vital, especially when vaccine is limited or unavailable
Keywords: 65+ years old; Ablation; Acute; Address; Adoptive Transfer; Affect; Age; Age-Years; Aged 65 and Over; Animal Model; Animal Models and Related Studies; Antibodies; Apoptosis; Apoptosis Pathway; Body Weight decreased; C57BL/6 Mouse; CTL; Cause of Death; Cell Communication and Signaling; Cell Count; Cell Death, Programmed; Cell Function; Cell Growth in Number; Cell Multiplication; Cell Number; Cell Process; Cell Proliferation; Cell Signaling; Cell physiology; Cell-Mediated Lympholytic Cells; Cells; Cellular Function; Cellular Infiltrate; Cellular Physiology; Cellular Process; Cellular Proliferation; Cessation of life; Cytokine Receptors; Cytolysis; Cytolytic T-Cell; Cytotoxic T Cell; Cytotoxic T-Lymphocytes; Cytotoxic cell; Data; Death; Defect; Dendritic Cells; Dependence; Dose; Elderly; Elderly, over 65; Environment; Exhibits; Family suidae; Flu vaccination; Future; Gamma Globulin, 7S; Goals; Grippe; H1N1 Virus; HOSP; Histology; Homing; Hospitalization; Human; Human, General; IgG; Immune; Immune response; Immunoglobulin G; Individual; Infection; Infiltration; Influenza; Influenza A Virus, H1N1 Subtype; Influenza Virus; Influenza immunization; Influenza vaccination; Intracellular Communication and Signaling; K lymphocyte; Leucocytic infiltrate; Lung; Lysis; Lytic; Lytotoxicity; Mammals, Mice; Man (Taxonomy); Man, Modern; Measures; Mice; Murine; Mus; NK Cell Activation; NK Cells; Natural Killer Cell Activation; Natural Killer Cells; Pathology; Persons; Pigs; Pneumonia; Pneumonitis; Population; Predisposition; Prevalence; Production; Prophylactic vaccination against influenza; Pulmonary Inflammation; Recovery; Reporting; Research; Resistance; Respiratory System, Lung; Role; Science of Statistics; Signal Transduction; Signal Transduction Systems; Signaling; Statistics; Subcellular Process; Suidae; Susceptibility; Swine; T-Lymphocytes, Cytotoxic; Therapeutic; Transgenic Mice; United States; Vaccines; Veiled Cells; Viral Diseases; Virus; Virus Diseases; Viruses, General; Vulnerable Populations; Weight Loss; Weight Reduction; advanced age; age dependent; age related; aged; base; biological signal transduction; body weight loss; cytokine; cytotoxicity; elders; flu immunisation; flu infection; geriatric; host response; human old age (65+); immunoresponse; in vivo; influenza infection; influenzavirus; influenzavirus (unspecified); late life; later life; model organism; mouse model; novel; older adult; older person; porcine; prophylactic; public health relevance; pulmonary; receptor function; resistant; response; seasonal influenza; senior citizen; social role; statistics; suid; viral infection; virus infection; wt-loss
Relevance: The prevalence of seasonal influenza and the recent emergence of swine 2009-H1N1 mandate the need to study age-related changes in the primary response to influenza infection. Aged mice show decreased NK cell function and elevated lung virus titers during the first four days of infection, and more importantly, die prior the initiation of an adaptive primary response. If applicable to humans, this suggests that the ability of young and aged individuals to mount an early and effective NK cell response to influenza infection is vital, especially when vaccine is limited or unavailable
Project start date: 2010-09-15
Project end date: 2015-06-30
Budget start date: 15-SEP-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-07-070
1R01AG034949-01A1 (2010): $365388