REJUVENATION OF THE T-CELL COMPARTMENT IN AGING PRIMATES

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 免疫系统的老化伴随着对广泛病原体的免疫防御能力的减弱，特别是那些宿主以前从未遇到过的病原体。这在临床上与传染病发病率和死亡率的增加有关，在65岁及以上的人中，传染病一直位居死亡原因的前五位。目前，免疫衰老的原因或干预点还没有确定。与年龄相关的最一致和最戏剧性的变化是T细胞动态平衡和功能的变化。随着年龄的增长，T细胞免疫功能的严重缺陷已经被很好地记录下来，重要的是，改善T细胞功能通常可以恢复老年动物的免疫防御，认为T细胞缺陷在免疫老化中起着关键作用。T细胞老化的主要标志包括NAVE的丧失和效应记忆T细胞的积累。由于胸腺退化和外周T细胞亚群的失调维持，T细胞的产生减少。正常情况下负责防御新的和重新出现的病原体的自然T细胞群体受到这种失调的极大影响，恢复自然T细胞的产生和维持被广泛认为是抗击免疫衰老的关键目标。因此，这项建议的目标是测试两种生长因子KGF和IL-7单独和联合使用改善老年自然T细胞产生和维持的能力。在这项研究的第一年，我们完成了4个实验，以确定IL-7或KGF扩展RM中天然(和记忆)外周T细胞的能力。IL-7已被证明通过外周(非胸腺)机制短暂地扩大NA？VE T细胞隔间。IL-7还起到了扩大中央记忆隔间的作用，而且这些作用更持久。到目前为止，KGF在所进行的研究中尚未被证明有效，但一项高剂量研究的结果目前仍在等待中。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Aging of the immune system is accompanied by weakening of immune defense against a wide spectrum of pathogens, particularly those that have not been previously encountered by the host. This clinically correlates with increased morbidity and mortality from infectious diseases, which consistently rank in the top five causes of death amongst those 65 and older. Neither the causes of, nor the points of intervention against, immune senescence has been defined at the present. Amongst the most consistent and most dramatic age-related changes are those that occur in T-cell homeostasis and function. Profound defects in T-cell immunity with aging have been well documented, and, importantly, improving T-cell function usually restores immune defense in aged animals, arguing that T-cell defects play a key role in immune aging. Cardinal signs of T-cell aging include loss of na¿ve and accumulation of effector memory T-cells. There is diminished T-cell production due to thymic involution and dysregulated maintenance of peripheral T-cell subsets. Na¿ve T-cell populations, which are normally in charge of defending against new and re-emerging pathogens, are dramatically affected by this dysregulation, and restoration of na¿ve T-cell production and maintenance is widely considered to be a crucial goal in combating immune senescence. The goals of this proposal are therefore to test the ability of two growth factors, KGF and IL-7, alone and in combination, to improve na¿ve T-cell production and maintenance in old age. In the first year of this study we have completed 4 experiments to determine the ability of IL-7 or KGF to expand the na¿ve (and memory) peripheral T cell compartment in RM. IL-7 has been demonstrated to transiently expand the na¿ve T cell compartment via a peripheral (non-thymic) mechanism. IL-7 also acts to expand the central memory compartment and these effects are more prolonged. KGF has not proven effective in the studies performed to date, but results of a high dose study are currently pending.