Healthy aging and latent infection with CMV lead to distinct changes in CD8+ and CD4+ T-cell subsets in the elderly.

Despite general acceptance that immunologic changes are associated with aging and latent infection with Cytomegalovirus (CMV), no clear-cut distinction has so far been made between strictly age-related and CMV-induced changes. We therefore compared CD4+ and CD8+ naïve (CD45RA+CD28+), memory (CD45RA-CD28+), and effector (CD28-) T cells in CMV-positive (n = 164) and CMV-negative (n = 87) elderly persons and correlated CD8+ and CD4+ effector T cells with other T-cell subpopulations. Percentages of CD8+ as well as CD4+ effector T cells were higher, but percentages of naïve and memory cells were lower in CMV-positive compared to CMV-negative elderly persons. Negative correlations within CD8+ T-cell subsets were found to be present in both CMV-positive and CMV-negative elderly individuals. In contrast, correlations within CD4+ T-cell subpopulations and a positive correlation between CD8+ and CD4+ effector T cells were found in CMV-positive individuals only. Our results demonstrate that (a) in the elderly different T-cell subsets compete for space within the CD8+, but not the CD4+ T-cell population; (b) CMV induces changes in the CD4+ compartment that differ from the solely age-related changes seen in CMV-negative elderly population; and (c) the CMV-status of a population has to be taken into account before a conclusion on the effect of aging on the composition of the T-cell pool can be reached.

Booster vaccination in the elderly: their success depends on the vaccine type applied earlier in life as well as on pre-vaccination antibody titers.

BACKGROUND: Recent retrospective studies demonstrate that elderly persons have a shortened protection period following vaccination with recall antigens. METHODS: We now analysed the effect of booster vaccination with a multivalent vaccine containing tetanus, dipththeria, pertussis and polio antigens in 252 healthy elderly persons. The magnitude of the humoral immune response was assessed by antibody measurements. RESULTS: Comparison with a small control group of 21 younger persons demonstrates that pre- and post-vaccination antibody concentrations are lower in elderly persons for all antigens except polio, for which higher pre- and similar post-vaccination antibody levels are observed. Using multiple linear regression analysis we also show that the magnitude of the humoral immune response in elderly persons greatly depends on pre-vaccination antibody concentrations in the case of tetanus, diphtheria and pertussis, but much less so in the case of polio, against which priming and preceding booster immunizations were performed with attenuated live vaccine. CONCLUSION: Regular booster vaccinations throughout life are of clinical importance to maintain the ability to respond to recall antigens in old age. Longer lasting protection and good responsiveness to boosting in spite of low antibody titres can be expected following exposure to live vaccine earlier in life.

Age-related differences in phenotype and function of CD4+ T cells are due to a phenotypic shift from naive to memory effector CD4+ T cells.

Based on the combined expression of CD27 and CD28, a putative model of T cell differentiation has been previously proposed. We used CD27 and CD28 expression in order to comparatively study the size, cytokine production capacity and proliferative response of CD4+ T cell sub-populations from healthy young and elderly volunteers. Elderly persons had a lower percentage of CD27+CD28+ but a higher percentage of CD27-CD28+ and CD27-CD28-CD4+ T cells than the young persons. CD27-CD28-CD4+ T cells were present, although at relatively low numbers, in the vast majority of the healthy elderly donors but were only sporadically detected in young persons. Each CD4+ T cell sub-population exhibited a distinct phenotype and cytokine production profile, which were not affected by age. When purified CD27+CD28+ were stimulated by staphylococcal enterotoxin B, they proliferated to a greater extent than CD27-CD28+ and CD27-CD28-CD4+ T cells. However, we did not observe age-related differences in proliferative response of each sub-population. We concluded that although the size of the different sub-populations differed between the young and the old group, the functional characteristics of each sub-population were the same in both age groups. This suggests that on a per cell basis there is no functional impairment of CD4 memory T cells in elderly persons. Consequently, potential differences in the function of the total CD4+ T cell population are most likely due to different composition of repertoire.

Reinforcing effect of subcutaneous morphine in a modified Ettenberg runway.

Alley running has been successfully used as an operant to demonstrate both the positive and negative reinforcing effect of intravenously administered drugs of abuse in a bona fide operant conditioning paradigm, the Ettenberg runway, in which confounding drug effects on motor performance and drug accumulation are avoided. While Ettenberg and colleagues focus on the intravenous route of drug administration, we tested the practicability of the subcutaneous route of administration in this runway paradigm in Sprague Dawley rats, using morphine as the investigated drug of abuse. We also modified the Ettenberg runway, most notably in that either food (sweetened condensed milk), no food, morphine, or saline was presented outside the runway in a separate cage. This made shaping, i.e., the initial presentation of a food reinforcer within the runway, necessary to establish responding. The manipulations necessary to administer subcutaneous (sc) injections were well tolerated by over 90% of the tested rats (n = 93). However, sc injections increased runtimes to the experimenter cutoff of 60 s within 20 once-daily sessions. Because of strong experimenter effects, all morphine doses or saline had to be adminstered blind. Under these experimenter-blind conditions, 0.1 and 1 mg/kg subcutaneous morphine proved to be reinforcing in that these doses significantly slowed down the gradual increase in runtimes imposed upon by the sc injection procedure. Thus, morphine can be demonstrated to be a positive reinforcer in a modified Ettenberg runway even when given subcutaneously. This effect, however, is eventually overcome by the negative reinforcing effect of subjecting the animals to sc injection procedure.