This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.
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