Characterization of Immune Alterations Associated with t

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Age-associated changes in immune function in humans and animals are quite important with regard not only to the general health of aged persons but also to the general features of the immune system itself. Elderly subjects have been shown to be more susceptible to viral and bacterial infections and are believed to be more susceptible to cancer. There have been a number of hypotheses for the diminished immune responses observed in elderly subjects including involution of the thymus, active immunosuppression, replication senescence of immune cells, cellular signaling defects, and alterations in cytokine expression profiles. A series of clinical studies has revealed that elderly subjects, in contrast to their younger counterparts, exhibit poor cellular and humoral immune responses to vaccines even in the presence of standard adjuvants. Currently, many laboratories are focusing their research efforts into developing more effective stimulants for use with known vaccines to be tested with elderly populations. However, the poor description of alterations in innate and acquired immune function during the aging process has limited therapeutic intervention. The current project utilizes peripheral white blood cells obtained from normal healthy volunteers of different ages to gain insight into the biological, biochemical, and molecular mechanisms underlying age-associated changes in human immune function. In comparison with immune cells obtained from younger individuals, aged leukocytes also display distinctive patterns of protein phosphorylation, cytokine synthesis and gene expression, effects on cell migration and trafficking, and cell-cycle progression. In addition, studies are currently underway examining primary and clonal cultures of CD28- and CD57+ T cells cultures isolated from humans and primates of different ages. As these immune subpopulations are dramatically increased in the circulation during various disease states (including arthritis, AIDS, and aging), we believe that more detailed molecular and biochemical analysis of these subsets will not only yield valuable information about the immune deficits associated with aging and disease but may also lead to possible immunotherapeutic interventions to boost immune responses. More specific efforts are also underway examining the differences in the make-up of lipid rafts within the cell membranes of young and aged lymphocytes. Given the large number of alterations in lipid peroxidation and metabolism with age, changes in the types, saturation and levels of various membrane sphingolipids, fatty acids and cholesterol may result in specific changes in membrane fluidity, protein association and aggregation, cellular activation and function. In addition, through HPLC separation, 2-D gel electrophoresis and mass spectroscopy, additional studies are underway creating a proteomic expression profile of the various proteins within the lipid rafts of young and aged lymphocytes at various stages of activation. We believe that a greater understanding of the various signaling and cell surface proteins associated with lipid rafts may provide great insight into age-related alterations in cell signaling and activation. Due to limits on human leukocyte availability from aged donors, we have focused some of our efforts on animal models and have demonstrated significant age-related phenotypic and molecular changes in both murine and primate T-cells and accessory cells.