T-CELL IMMUNITY TO NEW ANTIGENS IN PRIMATE SENESCENCE

灵长类衰老过程中 T 细胞对新抗原的免疫

• 批准号: 6783963
• 负责人: JANKO Z. NIKOLICH
• 金额: $ 22.33万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6783963
• 关键词: Macaca mulatta; T lymphocyte; aging; animal old age; antigens; biological models; cell population study; cell proliferation; cellular immunity; clone cells; cytotoxic T lymphocyte; gene expression; gene expression profiling; helper T lymphocyte; immune response; immunization; immunosenescence; infant animal; leukocyte activation /transformation; longitudinal animal study; mature animal; microarray technology; pathologic process

Aging of the immune system leads to diminished ability to respond to and clear pathogens and tumors believed to significantly contribute to morbidity and mortality in older individuals. It has been repeatedly shown that numerous T-cell functions are diminished or dysregulated in old age, however, despite intense research, gaps in the understanding of T-cell senescence still exist. Specifically, we do not fully understand the nature of homeostatic changes, the distinction between primary and secondary changes, nor the relative influence and the interplay between cellular and microenvironmental changes. This lack of knowledge precludes identification of the effective points of intervention to circumvent or reverse the age-related defects in immune function. The above gap in understanding T-cell senescence is still more pronounced as it relates to human senescence. To bridge the above gap, this project proposes to study in RM the evolution with age of T-cell response to new antigens by monitoring them following primary, secondary, memory and recall phases of the response. CD4 and CD8 T-cell responses will be measured by testing key phenotypic and functional parameters, in T-cells, including activation, in vivo proliferation and turnover, and development and maintenance of effector function. All experiments will evaluate strength (response intensity), threshold (sensitivity to different Ag doses) and kinetics of the response. Thereby, they will test a main hypothesis: that the key defect(s) lies in qualitative changes in naive CD8 T-cell responses; and two secondary hypotheses: (i) that T-cell clonal expansions (TCE) are associated with impaired primary T-cell responses; and (ii) that age-related dominance of memory CD8 T-cells is in part due to accumulation of Ag-specific cells with blunted effector function. Results from these studies should bring closer the long-term goal of this project, to improve T-cell immunity in the elderly.

免疫系统的衰老导致对响应和清除病原体和肿瘤的反应能力降低，这些病原体和肿瘤可显着促进老年人的发病率和死亡率。反复表明，在老年时，许多T细胞功能会降低或失调，但是，尽管进行了激烈的研究，但仍存在对T细胞衰老的理解差距。具体而言，我们不完全理解体内稳态变化的性质，主要和次要变化之间的区别，也不完全理解相对影响以及细胞和微环境变化之间的相互作用。缺乏知识排除了对干预措施的识别，以绕过或扭转免疫功能中与年龄相关的缺陷。理解T细胞衰老的上述差距仍然更为明显 它与人类衰老有关。为了弥合上述差距，该项目建议通过在反应的主要，次要，记忆和回忆阶段监测对新抗原的T细胞响应年龄进行RM研究。 CD4和CD8 T细胞响应将通过测试关键表型和功能参数（包括激活，体内增殖和周转）以及效应子功能的开发和维护来测量。所有实验将评估强度（响应强度），阈值（对不同AG剂量的敏感性）和反应动力学。因此，他们将检验一个主要假设： 关键缺陷在于幼稚CD8 T细胞反应的定性变化；和两个次要假设：（i）T细胞克隆膨胀（TCE）与主要T细胞反应受损有关； （ii）记忆CD8 T细胞与年龄相关的优势部分是由于具有钝化效应子功能的Ag特异性细胞的积累。这些研究的结果应更接近该项目的长期目标，以提高老年人的T细胞免疫力。