ENHANCING AGED CD4 COGNATE FUNCTION WITH CYTOKINES

用细胞因子增强老年 CD4 的同源功能

• 批准号: 7459706
• 负责人: Laura Haynes
• 金额: $ 45.19万
• 依托单位: TRUDEAU INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2008-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7459706
• 关键词: Address; Adjuvant; Adoptive Transfer; Affect; Age; Age-Months; Animals; Antibodies; Antibody Formation; Antibody-mediated protection; Antigens; Applications Grants; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Cell Aging; Cell physiology; Cell surface; Cells; Cessation of life; Columbidae; Communicable Diseases; Data; Defect; Development; Elderly; Enhancing Antibodies; Environment; Event; Exhibits; Generations; Goals; Grant; Hospitalization; Human; Immune response; Immune system; Immunization; In Vitro; Infection; Inflammatory; Influenza; Interleukin-2; Lead; Longevity; Memory; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; NF-kappa B; NP protein; Numbers; Peptide Fragments; Peptides; Persons; Phenotype; Population; Production; Proteins; Published Comment; Publishing; Risk; Signal Transduction; T memory cell; T-Cell Receptor; T-Lymphocyte; TNFRSF5 gene; Testing; Text; Transgenes; Transgenic Mice; Transgenic Model; Transgenic Organisms; Virus; Virus Diseases; Work; age effect; age related; aged; aluminum sulfate; base; cell age; cell type; chemokine receptor; cytochrome c; cytokine; day; flu; improved; improved functioning; in vivo; infectious disease model; normal aging; programs; receptor; research study; response; transcription factor; vaccine efficacy

Enhancing aged CD4 cognate function with cytokines. Immunization of the elderly is critically important since it can reduce the morbidity associated with infectious disease seen in the aged. The problem is that vaccine efficacy can be decreased 60 to 70% in the aged. This is extremely important since elderly persons exhibit a much increased risk of hospitalization and death from infectious diseases, such as influenza, compared to younger persons. We have used a T cell receptor transgenic (TCR Tg) model to examine how age affects CD4 function. The advantage of TCR Tg models is that they allow us to directly compare the in vitro and in vivo function of homogenous populations of antigen-specific CD4 cells from young and aged mice. By using these models, we can eliminate some of the differences in young and aged populations, such as the proportion of memory to naive cells that increases with age. In preliminary studies, we have shown that naive Tg CD4 cells from aged mice produce less IL-2 upon in vitro TCR stimulation compared to young cells. This has a profound impact on the initial expansion of naive aged cells and on subsequent differentiation of effectors. Furthermore, we have shown that these aged defects in expansion and cytokine production also occur in vivo in an adoptive transfer model. In vivo, decreased CD4 function due to aging could potentially impact both B cell and CTL responses. In fact, our studies show that there is a profound defect in the cognate helper function of aged CD4 cells. The goal of this grant proposal is to determine if exogenous cytokines or adjuvants can improve the function of aged CD4 T cells. We have determined that the aged CD4 defect in expansion and IL-2 production is overcome by immunization with adjuvants that induce inflammatory cytokines or by the cytokines themselves. In this grant, we will examine the effects of these cytokines on the in vitro and in vivo function of aged CD4 cells. We will examine how cytokines can act to enhance IL-2 production by aged CD4 cells in vitro. We will l also determine if cytokines or adjuvants can improve cognate helper function--including the impact on antigen-specific antibody production and induction of protective antibodies, as well as cognate help for CD8 responses. These studies will provide us with valuable information on how to improve the in vivo function of antigen-specific CD4 cells in the aged.

增强老年CD4与细胞因子同源功能。老年人的免疫接种至关重要，因为它可以减少老年人中与传染病相关的发病率。问题是，疫苗的效力在老年人中可能下降60 - 70%。这一点极为重要，因为与年轻人相比，老年人因流感等传染病住院和死亡的风险要大得多。我们使用了T细胞受体转基因（TCR Tg）模型来研究年龄如何影响CD4功能。TCR - Tg模型的优势在于，它允许我们直接比较体外和体内的功能