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.

通过细胞因子增强老化的CD4同源功能。老年人的免疫非常重要，因为它可以减少与年龄相关的传染病相关的发病率。问题在于，老年人可以降低60％至70％的疫苗功效。这是非常重要的，因为与年轻人相比，老年人表现出高大增加了流感疾病（例如流感）的住院风险和死亡的风险。我们已经使用了T细胞受体转基因（TCR TG）模型来检查年龄如何影响CD4功能。 TCR TG模型的优点是，它们允许我们直接比较体外和体内功能 来自年轻小鼠和老年小鼠的抗原特异性CD4细胞的同质种群。通过使用这些模型，我们可以消除年轻人和老年人群的某些差异，例如记忆与随着年龄增长的天真细胞的比例。在初步研究中，我们表明，与幼小细胞相比，体外TCR刺激后，来自老年小鼠的天真TG CD4细胞产生的IL-2较少。这对幼稚老化细胞的初始扩张以及随后的效应子的分化有深远的影响。此外，我们已经表明，这些膨胀和细胞因子产生中的这些老化的缺陷也在接收转移中发生 模型。在体内，由于衰老而导致的CD4功能降低可能会影响B细胞和CTL响应。实际上，我们的研究表明，老化CD4细胞的同源辅助功能存在严重的缺陷。该赠款建议的目的是确定外源性细胞因子或佐剂是否可以改善老化的CD4 T细胞的功能。我们已经确定，通过用诱导炎症细胞因子或细胞因子本身的辅助物免疫来克服膨胀和IL-2产生的老化CD4缺陷。在这笔赠款中，我们将研究这些细胞因子对老化CD4体外和体内功能的影响 细胞。我们将研究细胞因子如何在体外通过老化的CD4细胞增强IL-2产生。我们还将确定细胞因子或佐剂是否可以改善同源辅助功能 - 包括对抗原特异性抗体产生的影响以及保护性抗体的诱导以及COGNATE对CD8反应的帮助。这些研究将为我们提供有关如何改善老年抗原特异性CD4细胞体内功能的宝贵信息。