2002 — 2004 |
Kohut, Marian L |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Exercise &Influenza Immunity:Psychoneuroendocrine Model
DESCRIPTION (provided by applicant): The purpose of the proposed study is to investigate the effects of a regular, moderate exercise program on the immune response to influenza immunization in older adults; and to determine whether the mechanisms of the exercise-induced immunomodulation involve psychosocial and/or neuroendocrine adaptations. Older adults experience a greater incidence and severity of influenza infection, as well as reduced vaccine efficacy. We hypothesize that exercise will enhance immune response to the vaccine and improve psychosocial state. A total of 72 men and women > age 65 will be assigned to an exercise (EX), n=36, or control (CON) group, n=36. An additional 32 subjects (n= 16 EX, n=16 CON) currently treated with non-selective beta-adrenergic receptor antagonists will be recruited to test the hypothesis that the immunomodulatory effects of exercise are mediated via catecholamine activation of beta-adrenergic receptors. Subjects will be immunized with influenza vaccine and will be randomly assigned to participate in either a regular vigorous aerobic exercise program (EX) or a flexibility program (CON) for one year. Blood samples will be taken pre and post-immunization. At the end of one year, subjects will be immunized again and blood samples will be taken pre-immunization and up to 6 months post-immunization. Psychosocial measures of depression, perceived stress, social support, positive/negative affect, and daily hassles/uplifts will be assessed numerous times throughout the study. The primary immune outcome measures are: anti-influenza IgG and IgG1, influenza specific peripheral blood mononuclear cell proliferation and cytokine (interleukin (lL)-2, IL-10, interferon (IFN)-gamma) production, cytotoxic T lymphocyte (CTL) function, and intracellular influenza-specific IL-2, IL-b 0, IFN-gamma, in CD4+, CD8+, CD45RA+ and CD45RO+ cells. Growth curve modeling will be used to analyze the relationship between treatment condition and changes in the measures of immunocompetence over time. The findings from this study may have relevance from both a clinical and basic research perspective, if moderate exercise is associated with enhanced anti-influenza immunity and improved protection from infection.
|
1 |
2007 — 2009 |
Kohut, Marian L |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Exercise-Induced Immunomodulation in the Aged
[unreadable] DESCRIPTION (provided by applicant): A significant decrease in immune responsiveness occurs with advancing age. The clinical consequences of immunosenescence include an increased susceptibility to and/or severity of infectious disease. Several intervention strategies have been proposed to restore immune function. One of the least well-studied approaches to improve immune response is physical exercise. The long term research objectives of our research group are to elucidate the mechanisms underlying the adaptations induced by moderate exercise that enhance immune responsiveness to infectious disease in aged populations. In this application, one goal is to determine the mechanistic adaptations induced by exercise that affect the initial pathways involved in recognition of viral infection that result in enhanced IFNalpha production. A second goal is to identify which of the pathways that can be triggered by IFNalpha lead to improved viral clearance and reduced immunopathology. The specific aims are: 1) Identify the mechanism(s) by which exercise training of aged animals increases IFNalpha production after influenza virus challenge, 2) Determine the extent to which the exercise-induced increase in IFNalpha regulates responses of dendritic cells and CD8+cells, 3) Identify the pathways involved in the response to IFNalpha that are altered by exercise, and 4) Further define the impact of exercise by determining the balance between pro-inflammatory / anti-inflammatory cytokines within the lungs and the subsequent effect on immunopathologically-mediated tissue damage, identify the cells producing these cytokines, and establish the role of IFNalpha as a mediator of these effects. A mouse model of influenza viral infection will be used. Aged BALB/c mice will be assigned to a moderate exercise group for 10 weeks or a non-exercise group. After exercise training, some experiments will involve an in vivo viral challenge to examine immune responses that occur in the intact animals, whereas other experiments will involve the collection of cells from mice after exercise training, and exposure to viral challenge in vitro. Different techniques will be used to identify the type of cells responding to challenge as well as the multiple pathways involved. Upon completion of these studies, we expect to indentify the exercise-induced adaptations involved in cellular defense against viral infection that subsequently shape the evolving immune response resulting in improved viral clearance and reduced immunopathology. [unreadable] [unreadable] [unreadable]
|
1 |
2010 — 2011 |
Kohut, Marian L |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Exercise-Induced Immunomodulation in the Aged: Mechanisms
DESCRIPTION (provided by applicant): A significant decrease in immune responsiveness occurs with advancing age. The clinical consequences of immunosenescence include an increased susceptibility to and/or severity of infectious disease. Several intervention strategies have been proposed to restore immune function. One of the least well-studied approaches to improve immune response is physical exercise. The long term research objectives of our research group are to elucidate the mechanisms underlying the adaptations induced by moderate exercise that enhance immune responsiveness to infectious disease in aged populations. In this application, one goal is to determine the mechanistic adaptations induced by exercise that affect the initial pathways involved in recognition of viral infection that result in enhanced IFNalpha production. A second goal is to identify which of the pathways that can be triggered by IFNalpha lead to improved viral clearance and reduced immunopathology. The specific aims are: 1) Identify the mechanism(s) by which exercise training of aged animals increases IFNalpha production after influenza virus challenge, 2) Determine the extent to which the exercise-induced increase in IFNalpha regulates responses of dendritic cells and CD8+cells, 3) Identify the pathways involved in the response to IFNalpha that are altered by exercise, and 4) Further define the impact of exercise by determining the balance between pro-inflammatory / anti-inflammatory cytokines within the lungs and the subsequent effect on immunopathologically-mediated tissue damage, identify the cells producing these cytokines, and establish the role of IFNalpha as a mediator of these effects. A mouse model of influenza viral infection will be used. Aged BALB/c mice will be assigned to a moderate exercise group for 10 weeks or a non-exercise group. After exercise training, some experiments will involve an in vivo viral challenge to examine immune responses that occur in the intact animals, whereas other experiments will involve the collection of cells from mice after exercise training, and exposure to viral challenge in vitro. Different techniques will be used to identify the type of cells responding to challenge as well as the multiple pathways involved. Upon completion of these studies, we expect to indentify the exercise-induced adaptations involved in cellular defense against viral infection that subsequently shape the evolving immune response resulting in improved viral clearance and reduced immunopathology.
|
1 |
2021 |
Kohut, Marian L Narasimhan, Balaji (co-PI) [⬀] |
R01Activity Code Description: To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Combination Ovaccine-Based Immunization Against Influenza Virus in the Aged: Immunity and Protection
PROJECT SUMMARY / ABSTRACT Age-related defects of the immune response contribute to reduced efficacy of the influenza vaccine in older adults. Influenza A virus (IAV) infection results in greater risk of complications and higher hospitalization rates in older adults, with approximately 90% of deaths occurring in adults over age 65. Therefore, the development of a safe and effective vaccine that promotes protective immunity for the aged is an urgent public health need. The overall goal of this revised R01 application is to identify the effect of vaccine biomaterials and adjuvants on DC metabolism, and subsequent effects on antibody and T cell memory to develop a nanovaccine to overcome age-related immune impairments. Vaccines for older adults can be further optimized with biomaterials that enhance multiple arms of the immune system and provide a platform to expand antigen selection, broadening protection. Our studies will establish the contribution of specific biomaterials and adjuvants in improving B and T cell outcomes resulting in protection by enhancing vaccine efficacy. The goals are to: 1) develop an efficacious influenza nanovaccine for older populations; and 2) to understand the mechanisms by which rational selection of biomaterials and co-adjuvants in vaccines can enhance immune capabilities of aged individuals. Our two polymeric nanovaccine platforms, polyanhydride nanoparticles and pentablock copolymer micelles, have been shown to increase antibody titers, improve cell-mediated immunity, and prolong antigen delivery resulting in a protective immune response with reduced viral load upon delivery of recombinant hemagglutinin and nucleoprotein in an IAV challenge model. Compelling preliminary data demonstrates that these formulations differentially alter dendritic cell (DC) metabolic profile compared to traditional adjuvants. Aim 1 will identify how nanovaccine biomaterials and adjuvants that promote DC metabolic health augment the immune response in aged mice. Different vaccine formulations will compare adjuvants that produce high glycolytic responses with formulations that retain some oxidative phosphorylation and spare respiratory capacity to optimize DC function. In the second aim, we will optimize the nanovaccine formulation(s) that enhance B cell activation in aged mice and peripheral blood B cells from aged humans. Additionally, we will identify mechanisms by which our nanovaccine improves T follicular helper responses and the induction of protective immunity on an aging background. Traditional inactivated IAV vaccine will be used as a control so as to identify the formulation providing superior protection than the current vaccine. In Aim 3, we will determine how nanovaccine-induced metabolically-optimized DC-T cell priming contributes to T cell memory and heterologous protection against IAV in aged mice. Measures of viral load, serum antibody, and lung T cell responses will be evaluated in homologous and heterosubtypic IAV challenges in aged mice. The long-term goal of this research is to define the mechanisms responsible for induction of protective immune responses in aging populations, thus facilitating the rational design of improved vaccines for this underserved population.
|
1 |