T CELLS AND AGING

T 细胞与衰老

基本信息

批准号：
6372150
负责人：
JORG J GORONZY
金额：
$ 21.14万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-15 至 2003-06-30
项目状态：
已结题

项目摘要

DESCRIPTION (Adapted from the Applicant's Abstract): Aging is associated with important clinical problems such as increased susceptibility to infections and certain malignancies. Mechanisms underlying immunosenescence are not completely understood but evidence has been collected that T cell function declines in the elderly. The investigators have made the observation that, in a subset of aged individuals, CD4+ T cells have lost the expression of the important co-stimulatory molecule, CD28. Susceptibility to losing CD28 expression appears to be genetically determined and occurs in about 30% of the Caucasian population. The investigators have also shown that CD4+ CD28 null T cells are deficient in the expression of CD40 ligand (CD40L) and therefore lack a second critical molecule that is important in facilitating T-B cell interactions and the development of humoral immune responses. Preliminary data indicate that the downregulation of CD28 on CD4+ T cells is caused by a transcriptional block. The investigators have evidence that two possibly novel nuclear DNA binding activities correlate with CD28 expression and that the presence of these binding activities is age dependent. The investigators propose that the loss of CD28 is a critical event in immunosenescence and that understanding mechanisms of CD28 gene expression will provide novel agents for interventions intended to correct immune hyporesponsiveness in the elderly. The investigators are planning to examine the basal transcriptional machinery regulating CD28 gene expression and to identify the cis-acting elements required for CD28 expression. The investigators will continue their studies aimed at defining the binding motifs within a 67 bp segment and to molecularly characterize the corresponding DNA binding proteins that have been shown to correlate with CD28 expression. The investigators propose to clone and sequence the corresponding genes and to confirm differential expression in CD28+ and CD28null T cells. The influence of senescence on the expression of these proteins will be analyzed in vitro after replicative senescence as well as in vivo by comparing young and old individuals. Finally, the investigators will pursue the question whether CD40L expression can be restored by reconstituting CD28 expression in deficient T cells. This question will be examined by comparing helper cell functions of CD4+ CD28null and CD4+ CD28null T cell clones derived from the same progenitor cell and by transfecting CD28-deficient CD4+ T cell clones with the CD28 gene. Studying molecular and functional aspects of CD4+ CD28null T cells provides a unique opportunity to address age- related dysfunction in T cells. Preventing the accumulation of CD4+ CD28null T cells might be a primary target for immune therapy in aging individuals.

描述（改编自申请人的摘要）：衰老是相关的具有重要的临床问题，例如易感性增加感染和某些恶性肿瘤。免疫衰老的机制尚未完全了解，但已收集证据表明 T 细胞老年人的机能下降。调查人员已做出观察发现，在一部分老年人中，CD4+ T 细胞已经丢失重要的共刺激分子 CD28 的表达。 CD28 表达缺失的易感性似乎与遗传有关已确定并发生在约 30% 的白种人中。这研究人员还表明，CD4+ CD28 null T 细胞缺乏 CD40 配体 (CD40L) 的表达，因此缺乏第二个关键对促进 T-B 细胞相互作用很重要的分子体液免疫反应的发展。初步数据表明 CD4+ T 细胞上 CD28 的下调是由转录阻断引起的。研究人员有证据表明两种可能新颖的核 DNA 结合活性与 CD28 表达相关，并且这些的存在结合活性取决于年龄。调查人员建议 CD28 的丢失是免疫衰老中的一个关键事件，并且了解 CD28基因表达机制将为旨在纠正老年人免疫反应低下的干预措施。研究人员计划检查基础转录调节 CD28 基因表达的机制并鉴定顺式作用 CD28 表达所需的元件。调查人员将继续他们的研究旨在定义 67 bp 片段内的结合基序并对相应的 DNA 结合蛋白进行分子表征已被证明与 CD28 表达相关。调查人员建议克隆并测序相应基因并确认 CD28+ 和 CD28null T 细胞中的差异表达。的影响衰老对这些蛋白质表达的影响将在体外进行分析复制性衰老后以及体内通过比较年轻人和老年人个人。最后，调查人员将追问是否 CD40L 表达可以通过重建 CD28 表达来恢复 T细胞缺陷。这个问题将通过比较辅助细胞来检验 CD4+ CD28null 和 CD4+ CD28null T 细胞克隆的功能相同的祖细胞并通过转染 CD28 缺陷型 CD4+ T 细胞克隆带有CD28基因。研究 CD4+ 的分子和功能方面 CD28null T 细胞提供了解决年龄相关问题的独特机会 T 细胞功能障碍。防止 CD4+ CD28null T 积累细胞可能是老年人免疫治疗的主要目标。