Takashi Makinodan

Age influence on the immune system.

Publisher Summary This chapter discusses many observations indicating a decline in immune function with aging both in experimental animals and in humans. It is evident that a decline in T cell function gradually occurs and this affects the entire immune system. Antibody formation and B cell function appear to be secondarily altered. Various autoantibodies are increased in older experimental animals and humans that may relate to the observed decrease in suppressor cells. Cell-mediated immunity has been analyzed in vivo and in vitro. Various T cell-dependent functions decline with age. Normal immune functions can begin to decline as early as when an individual reaches sexual maturity. The decline is due to changes in the immune cells and their milieu. Cell loss, shift in the proportion of subpopulations, and qualitative cellular changes, the three possible types of changes that can cause the decline, have all been detected.

Immunologic basis for susceptibility to infection in the aged.

Age-related immune dysfunction contributes to the vulnerability of old individuals to infection, e.g., animal model studies demonstrate the association between age-related decline in T cell-dependent immunologic responses and the decline in resistance against viral, bacterial, and parasitic infections. This review briefly describes age-related changes in the immune system at the systemic, tissue and cellular levels. At the systemic level, emphasis is on polymorphic effects of aging; at the tissue level, emphasis is on the vulnerability of primary tissues engaged in the generation of antigen-responsive cells and on the difference in the onset and rate of changes between different peripheral tissues of the system; and at the cellular level, emphasis is on the qualitative changes at the surface receptor, cytoplasmic and nuclear levels.

Age-related impaired proliferation of peripheral blood mononuclear cells is associated with an increase in both IL-10 and IL-12.

Reflective of age-associated decline in immune function among elderly individuals is a decrease in in vitro T cell proliferative ability. Impaired T cell proliferation in the elderly may result from disruption of the well-balanced network of regulatory cytokines produced during an immune response. The purpose of this study was to identify age-related changes in the production of interleukin (IL)-10 and IL-12, and to determine whether in vitro T cell proliferation can be enhanced in the elderly by modulation of these two key cytokines. The superantigen Staphyloccocus entertoxin B (SEB) was used to stimulate proliferation and IL-10 and IL-12 production in peripheral blood mononuclear cells (PBMC) in vitro. Proliferation was determined by standard tritiated thymidine uptake. Cytokine levels in culture supernatants were measured by ELISA. We observed impaired SEB-induced proliferation of PBMC in the elderly that is comparable to that seen with the polyclonal mitogen Con A. This age-related decline in proliferation was associated with increased production of both IL-10 and IL-12. Modulation of PBMC proliferative response with either recombinant IL-12 or IL-10-neutralizing antibodies can boost proliferation of elderly PBMC to the levels seen in unmodulated young controls.

Host Resistance and Immune Responses in Advanced Age

Immunosenescence results in populating immune tissues with less functional T cells, and perhaps B cells dendritic cells, that do not function well and produce more type 2 cytokines and fewer type 1 cytokines. Impaired immunity, distinct from immunosenescence, correlates more with disease burden than chronologic age. Older adults who have chronic diseases or chronic infections are more susceptible to common infections and have poor vaccine responses. Understanding specific mechanisms and targeting interventions are dependent on research to resolve the relationship between frailty-associated impaired immunity and the role of chronic infection versus immunosenescence in developing impaired immunity.

Influence of age of thymic grafts on the differentiation of T cells in nude mice

Abstract Age-related changes in the capacity of thymic grafts to promote T-cell differentiation were studied in congenic nude BALB/c mice. The results revealed that the cytolytic T-cell activity and T-cell-dependent anti-SRBC response declined exponentially with age, the former starting its decline at birth, and the latter after adulthood. In contrast, the T-cell-dependent mitogenic response to PHA and Con A stimulation and the number of Thy-1 + cells declined minimally with age of the thymic graft. These findings suggest that aging decreases the capacity of the thymus to synthesize the various factors needed for the generation of T-cell subpopulations differently with respect to the time of onset and rate of decline. In addition, results suggest that the aging thymus is also losing its ability to regulate natural killer cells.

Slower immune system aging in women versus men in the Japanese population

BackgroundGender-related differences in humans are commonly observed in behaviour, physical activity, disease, and lifespan. However, the notion that age-related changes in the immune system differ between men and women remains controversial. To elucidate the relationship between immunological changes and lifespan, peripheral blood mononuclear cells from healthy Japanese subjects (age range: 20–90 years; N = 356) were analysed by using three-colour flow cytometry. The proliferative activities and cytokine-producing capacities of T cells in response to anti-CD3 monoclonal antibody stimulation were also assessed.ResultsAn age-related decline in the number of T cells, certain subpopulations of T cells (including CD8+ T cells, CD4+CDRA+ T cells, and CD8+CD28+ T cells), and B cells, and in the proliferative capacity of T cells was noted. The rate of decline in these immunological parameters, except for the number of CD8+ T cells, was greater in men than in women (p < 0.05). We observed an age-related increase or increasing trend in the number of CD4+ T cells, CD4+CDRO+ T cells, and natural killer (CD56+CD16+) cells, as well as in the CD4+ T cell/CD8+ T cell ratio. The rate of increase of these immunological parameters was greater in women than in men (p < 0.05). T cell proliferation index (TCPI) was calculated from the T cell proliferative activity and the number of T cells; it showed an age-related decline that was greater in men than in women (p < 0.05). T cell immune score, which was calculated using 5 T cell parameters, also showed an age-related decline that was greater in men than in women (p < 0.05). Moreover, a trend of age-related decreases was observed in IFNγ, IL-2, IL-6, and IL-10 production, when lymphocytes were cultured with anti-CD3 monoclonal antibody stimulation. The rate of decline in IL-6 and IL-10 production was greater in men than in women (p < 0.05).ConclusionAge-related changes in various immunological parameters differ between men and women. Our findings indicate that the slower rate of decline in these immunological parameters in women than that in men is consistent with the fact that women live longer than do men.

Comorbidity is a better predictor of impaired immunity than chronological age in older adults.

Objectives: To determine whether high level of comorbidity, measured using a standardized instrument, can predict impaired immunity in older adults.

Veteran identity and race/ethnicity: Influences on VA outpatient care utilization

Background. “Veteran identity” is defined as veterans’ self-concept that derives from his/her military experience within a sociohistorical context. Veteran identity may vary by race/ethnicity because the sociohistorical context of the military experience varies by race. Objectives. To explore veteran identity and how it varies by race/ethnicity, and to identify aspects of veteran identity that significantly influence preferences for, and use of, VA outpatient care. Research Design. Focus groups were conducted at community sites to explore concepts related to veteran identity, race/ethnicity, military experience, and health services use. The focus groups informed the development of a telephone survey, which was administered to veterans of four racial/ethnic groups in Southern California and Southern Nevada. Subjects. One hundred seventy-eight veterans participated in the focus groups, and 3,227 veterans completed the telephone survey. Measures. Dependent variables include: (1) preference for VA health services, (2) VA-only outpatient use, (3) Any VA outpatient use, and (4) number of outpatient visits within the previous 12 months. Independent variables include veteran identity, sociodemographic, and health-related characteristics. Results. All veteran identity variables were significantly associated with race/ethnicity. Race/ethnicity, eg, being black or Hispanic, in addition to veteran identity factors, significantly influenced preferences for VA outpatient care. Veteran identity factors, however, had less influence on VA outpatient service utilization than socioeconomic factors. Conclusions. Minority veterans who highly identify with their veteran status may prefer the VA to other systems of care. Factors associated with veteran identity may be useful for incorporation into interventions to improve access to VA care.

In situ hybridization analysis of the age-associated decline in IL-2 mRNA expressing murine T cells.

Only a small decrease in the number of L3T4- cells was observed in the Con A-stimulated splenocyte cultures of old mice as compared to young, which cannot account for the threefold decrease in IL-2 production. Northern and dot blot analysis of RNA from splenocytes containing equivalent numbers of L3T4+ cells from young and old mice showed that cells from old mice express less IL-2 mRNA after mitogenic stimulation than cells from young mice. Direct analysis by in situ hybridization of stimulated splenocytes from young and old mice then showed approximately a threefold decrease in the percentage of IL-2 mRNA expressing cells in the spleens of old mice as compared to young (8.7 +/- 4.1% old; 28.7 +/- 11.7% young). The average level of expression of IL-2 mRNA was not significantly different between cells from young and old mice; however, there were approximately 40% fewer cells expressing an intermediate to high amount of IL-2 mRNA in old mice as compared to young (26.3% vs 41.8%). These data suggest that the decrease in IL-2 production with age is associated primarily with a decrease in the frequency of IL-2 mRNA-expressing cells in old mice, especially in those cells expressing intermediate to high levels of IL-2 mRNA.

Decline in the production of interleukin-3 with age in mice.

Previously, we and others have found that the ability to produce interleukin-1 (IL-1) and interleukin-2 (IL-2) declines with age in mice. The purpose of this study was to determine the influence of age on the capacity of mice to produce interleukin-3 (IL-3). Splenic cells (5 X 10(6)/ml) from young (3-4 months) and old (24-32 months) C57BL/6 mice were first assessed for their IL-3-producing capacities in response to varying doses of concanavalin A (Con A; 2-20 micrograms/ml) in a time-dependent manner. The results showed that the production of IL-3 by both young and old C57BL/6 mice was maximal on Days 3 and 4 in response to 20 micrograms/ml of Con A, and that of IL-2 was minimal (activity was less than 0.1 unit) on Day 4. Consequently, Day 4, was selected to assess the effect of age on IL-3 production by splenic cells. The results showed a twofold reduction in IL-3 production with age (P less than 0.05). Young-old splenic cell mixture experiments at ratios of 1:0, 3:1, 1:1, 1:3, and 0:1 indicated that the decrease in IL-3 production with age was not due to an increase in suppressor cell activity. Experiments based on mixtures of nylon wool-enriched splenic T-cell and adherent cells and on anti-MAC-1 plus complement-treated spleen cells indicated that (a) adherent cells are not required for T-cell production of IL-3, unlike IL-2 production, and (b) the decrease in IL-3 production with age is due solely to alteration in IL-3-producing T cells. Finally, a strong correlation was demonstrated between the production of IL-2 and IL-3 by spleen cells of individual young and old mice (r = 0.92, P less than 0.01). That production of both IL-2 and IL-3 is affected in a similar manner by age would suggest that a single class of helper T cells may be responsible for production of both lymphokines.