This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Higher susceptibility of the elderly to infectious diseases is associated with an age-related waning of immunity, termed immune senescence, which remains incompletely understood. This program project grant is a highly collaborative program whose goal is to define a sophisticated model of human immune aging in Rhesus macaques (RM), and apply this model to elucidate the mechanisms of underlying immune senescence. The overarching program hypotheses are that: 1) RM will provide an outstanding model for human immune senescence: and 2) immune aging is the composite result of changes in multiple interactive components of the immune system [T-cells, B-cells, dendritic cells (DC) and their interaction with environment (e.g., persisting infections)]. These studies will test the above hypotheses by assessing the evolution of, and mechanisms responsible for, immune senescence in RM. The Program contains four projects that will study age-related changes in: 1) DC immunity; 2) humoral immunity; 3) cellular immunity to new antigens; and 4) cellular immunity to persistent infection and reinfection. These projects are supported by four state-of-the-art cores that provide scientific integration and administration (A), expert management and coordination of all animal procedures (B), analysis of gene expression profiles (C), and bioinformatical and biostatistical data (D). Program design incorporates several unique features that justify the P01 format and enhance its value: 1) synergistic study of diverse immune parameters, using mixed cross-sectional and longitudinal follow-up in the very same RM, allowing cross-correlation of possibly inter-related changes in each individual; 2) comprehensive testing of all pertinent aspects of immunity will yield data on inter-related processes of antigen (Ag) capture, presentation, DC migration, B- and T-cell function (responses to acute and persistent Ag), allowing dissection of primary, secondary and tertiary changes; 3) highly qualified, interactive research team provides multidisciplinary approach to immune senescence; and 4) RM model and a cohort of rare aged animals makes possible critical manipulation to probe immune senescence and the future highly relevant preclinical testing of ways to improve immunity in the elderly. Long-term goals are to use these findings to improve protective immunity in old RM, and subsequently, elderly humans.
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