Donna M. Murasko

Role of humoral and cell-mediated immunity in protection from influenza disease after immunization of healthy elderly

While influenza immunization significantly reduces the risk of pneumonia and associated deaths, vaccination of elderly only affords 30-50% protection against influenza disease. The purpose of this study was to: (1) evaluate the consistency of immune responses across multiple years in young and elderly; (2) determine the contribution of antibody and cell-mediated responses in protection after immunization with influenza vaccine. Independently living healthy elderly (>200/year; mean age 78.8-80.6/year) were recruited yearly in this four year study. The results clearly demonstrate: (1) both young and elderly consistently produced significant antibody and T cell proliferative responses to influenza vaccine upon yearly immunization; however, both responses of elderly were significantly and consistently lower than young. (2) Percentages of both young and elderly demonstrating protective titers (i.e. HI>/=40) increased post-immunization each year, but were consistently higher in young compared to elderly. (3) The risk of developing influenza disease after immunization was highest among elderly demonstrating neither antibody nor cell-mediated responses. Importantly, the risk of influenza disease was comparable in elderly demonstrating a cell-mediated response alone, an antibody response alone, or both cell-mediated and antibody responses. This suggests that cell-mediated responses play a significant role in protection in at least a subset of elderly from influenza disease after immunization.

Immune response to influenza vaccination in a large healthy elderly population

Elderly individuals not only demonstrate a greater risk of morbidity and mortality from influenza than the young, but also have greater difficulty mounting a protective response to influenza vaccine. The mechanism of the decreased efficacy of influenza vaccination in the elderly is not well understood. The present study was designed to assess the interaction between cell-mediated and humoral immune responses to influenza vaccine in a large population (n = 233) of healthy elderly individuals (mean age = 80.7) living in six continuing care retirement communities (CCRCs). While influenza vaccination resulted in significant increases in the mean anti-influenza antibody titres and mean proliferative responses of peripheral blood mononuclear cells to purified subvirion trivalent influenza vaccine one month after vaccination, only 48.9% and 30.0% of subjects had intact humoral and cell-mediated immune responses, respectively. No association was observed between intact cell-mediated and humoral responses: 14.7% of subjects had an intact cell-mediated, but not humoral response, and 32.6% of subjects had an intact humoral, but not cell-mediated response. However, IFNgamma production was significantly correlated with both antibody and cell-mediated responses to influenza vaccination, a finding not previously reported in the elderly. These results indicate that there is considerable heterogeneity among immune responses of the elderly to influenza vaccination. This heterogeneity needs to be a major consideration in evaluation of new vaccine preparations.

Age-related changes in Type 1 and Type 2 cytokine production in humans.

Although aging is accompanied by several changes in immune function, altered T cell function represents the most consistent and dramatic change. Since cytokines modulate the immune response, it has been postulated that these age-associated changes in T cell function may be due to alterations in cytokine production. Data from murine studies generally support an age-related shift from a Th1-like (IL-2, IFN-γ) to a Th2-like (IL-4, IL-6,IL-10) cytokine response; however, whether or not such an age-related shift to a Type 2 cytokine response occurs in humans is not certain. This review of over 60 studies in humans, in which Type 1 and Type 2 cytokines were evaluated either alone or together, suggests that age-associated changes in cytokine production are inconsistent. Further, these age-associated changes in cytokine production do not always induce a shift to a Type 2 cytokine response. Importantly, these studies highlight that the stimulus used to induce cytokines influences both the level and pattern of immune response. Additional comprehensive evaluations in human studies are both critical and necessary to clearly identify the impact of altered cytokine production on age-related changes in immune function.

Immunologic response in an elderly population with a mean age of 85

Previous studies of changes in immune responses in the elderly have been limited in both number and age of elderly subjects and have produced conflicting results. Using 260 subjects, mean age 84.6, the present study conclusively demonstrates that T cell response is decreased in the elderly. Decreases in response to phytohemagglutinin and concanavalin A were demonstrated in groups aged 70 to 79, 80 to 84, and 85 to 89, although a group 90 to 106 years old showed a decreased response only to phytohemagglutinin. None of the groups had a decreased response to pokeweed mitogen. No response to all three mitogens was observed in 13 percent of the group aged 70 to 89, but in none of the group aged 90 to 106 or in the young groups. No differences in natural killer cell cytotoxicity were observed among the elderly groups. In contrast to previous studies, these results suggest that: the decreased immune response of the elderly is not directly related to age, over age 70; and there may be a selection process in which subjects who live to the age of 90 are those in whom the least decrease in immune response is demonstrated.

Age-associated decrease in virus-specific CD8+ T lymphocytes during primary influenza infection

The mechanism of the age-associated decrease in CD8+ T cell response of mice to virus infection was examined in young adult (6 months) and aged (22 months) C57BL/6 mice during primary pulmonary influenza A virus infection. A significant age-associated decrease in both the percentage (P<0.0001) and number (P<0.05) of CD8+ T cells binding MHC Class I tetramers containing influenza A nucleoprotein (NP) epitope and in virus-specific CTL activity (P<0.05) was observed with pulmonary lymphocytes. The percentage of NP+CD8+ cells of individual mice strongly correlated with NP-specific cytotoxic activity (r(2)=0.77, P<0.02) and with the percentage of CD8+ cells that produced interferon-gamma (r(2)=0.86, P<0.002) in both young and aged mice. Comparable expression of the CD28, CD25, and the memory CD44(hi)/CD62L(lo) phenotype was detected on NP+CD8+ lymphocytes from mice of both age groups. There was a delay in the maximal expansion of NP+CD8+ cells in aged compared to young mice that paralleled a delay in maximal cytotoxic activity and in virus clearance. These data suggest that the age-related impairment of CD8+ lymphocyte activity during a primary influenza A infection is due to a defect in the expansion, rather than in effector activity, of influenza-specific CD8+ T cells.

Cytokine production after influenza vaccination in a healthy elderly population

Influenza vaccination is less efficacious in the elderly than in the young. To characterize this age-related decrease in immune response to influenza vaccination, antibody and cell-mediated responses to influenza vaccine were assessed before immunization and 4 weeks after vaccination of a population of 270 healthy elderly individuals (mean age: 80.2 years) living in eight local continuing care retirement communities (CCRCs) and 30 young individuals (mean age: 27.8 years). The antibody titres produced against all three influenza strains increased significantly after vaccination in both the young and elderly (p < 0.0005); however, the young demonstrated significantly higher titres to all three strains than did the elderly (p < 0.03). Peripheral blood mononuclear cells (PBMC) cultured with influenza vaccine demonstrated significantly increased proliferation (elderly: p < 0.00005; young: p < 0.001) after vaccination, with proliferative responses in the young significantly higher than the elderly both before (p < 0.04) and after (p < 0.0005) vaccination. Similarly, IFN gamma production in these PBMC cultures increased significantly pre- to postvaccination in both young and elderly (young: p < 0.006; elderly: p < 0.00005), but the young produced more than the elderly both pre- and postvaccination (p < 0.0001). Following vaccination, PBMC production of IL-10 was higher in the young than in the elderly (p < 0.0015), while IL-6 production was comparable in both young and elderly individuals. Greater than 13% of the elderly population did not produce detectable IL-6, IL-10, or IFN gamma either before or after vaccination. The data show that the decreased cell-mediated and humoral responses to influenza vaccination of this healthy elderly population are accompanied by the production of lower levels of cytokines. A unique finding in this population of 270 healthy elderly was the association between a TH0 cytokine profile and intact immune responses to influenza vaccine. A similar relationship was not seen in the young.

Response of aged mice to primary virus infections

Summary:  Aging is associated with an increased morbidity to virus infections as well as a delay in clearance of symptoms after infection. Studies of sublethal virus infections of aged mice closely mirror the human situation: there is a delay in clearance of virus. The delay in virus clearance is accompanied by a delay and a decrease in T‐cell response, particularly of CD8+ T cells. Intrinsic alterations of T cells of aged mice contribute to this decrease in virus‐specific T‐cell response; however, evidence suggests that environmental or innate components of the aged host also influence this age‐associated decline in clearance of virus. While the changes in the adaptive immune response have been carefully described, the early events in the generation of the T‐cell response after virus infection have received limited attention. Importantly, age‐associated changes in the innate response to virus infection, particularly production of and response to interferon (IFN)‐α/β, cytotoxicity and IFN‐γ production by natural killer cells, interleukin‐12 induction, and depletion of non‐specific T cells early during virus infection need further evaluation.

Rapid Inactivation of Airborne Bacteria Using Atmospheric Pressure Dielectric Barrier Grating Discharge

Dielectric barrier discharge plasma has been known to inactivate many different microorganisms on surfaces when treatment times are on the order of seconds or minutes in duration. In this paper, a unique plasma air cleaning facility was created which combines a dielectric barrier grating discharge (DBGD) with a filterless laboratory-scale ventilation system and is used to treat concentrated bacterial bioaerosol in a moving air stream at air flow rates of 25 L/s. Results indicate that plasma treatment times on the order of milliseconds corresponding to one pass through the DBGD device can achieve 1.5-log reduction in culturable E. coli immediately after contact with plasma and 5-log reduction totally following in the minutes after the plasma treatment. A numerical characterization study was performed to help predict and understand the mechanism of bacteria inactivation in the DBD plasma from a variety of plasma factors.

Mechanisms of Caloric Restriction Affecting Aging and Diseasea

Caloric restriction (CR) appears to affect aging by the inhibition of the specific chronic diseases which occur at increasing frequency with age. A common disease in F-344 rats, granulocytic leukemia, appears to have a window where it is sensitive to the effects of CR. Other diseases, such as pituitary adenomas, appear to have a different relationship to growth in the animal. Additionally, a model for the major disease for a number of long-lived strains of mice, lymphoma, which CR effects by inhibiting the expression of the causative agent, is being developed. Evaluation of the effects of CR on neoplasia, degenerative disease and physiological parameters suggests that the major factors in expression of these diseases is the alteration of growth factors, hormonal status, etc., and that these alterations also affect strain-specific pathologies depending on when they are changed in the life span. Effecting different diseases at different times in the life span, long-term CR, by limiting exposure to endogenous growth factors, altering physiological characteristics, and limiting exposure to food toxicants, inhibits the onset of disease, and its sequela, aging.

Splenic and inguinal lymph node T cells of aged mice respond differently to polyclonal and antigen-specific stimuli

Numerous changes have been reported to occur in T cell responsiveness of mice with increasing age. However, most of these studies have examined polyclonal stimulation of spleen cells from a limited number of mouse strains. This study investigated the influence of genetic background, source of lymphocytes, and type of stimulus on age-associated changes in T cells response. Con A-induced proliferation and IL-2 and IFN-gamma production by splenic lymphocytes (SL) was significantly greater in CBA/Ca mice compared to C57BL/6 mice, regardless of age. SL of both strains exhibited the predicted age-dependent decline in proliferative response and an increase in IFN-gamma production in response to Con A. In contrast, however, only SL from C57BL/6 mice demonstrated the predicted age-dependent decline in Con A-induced IL-2 production; Con A-induced SL of young and aged CBA/Ca mice produced comparable amounts of IL-2. Differences in age-associated responses to Con A were also observed between SL and inguinal lymph node (ILN) cells of CBA/Ca mice. In contrast to SL, ILN cells demonstrated an increased proliferative response to Con A. However, lymphokine production by Con A-stimulated ILN cells from aged CBA/Ca mice was similar to that of Con A-stimulated SL from aged CBA/Ca mice. To determine if aged ILN T cells respond similarly to polyclonal and antigen-specific stimuli, keyhole limpet hemocyanin (KLH) responses of T cells isolated from ILN of aged and young CBA/Ca mice were examined. KLH-specific T cells from aged mice cultured with KLH-pulsed macrophages (M phi) from aged mice were significantly reduced in their ability to proliferate compared to KLH-specific T cells of young mice cultured with young KLH-pulsed M phi. In contrast to the expected results, the defect was not at the level of the T cells; proliferation of young T cells cultured with aged KLH-pulsed M phi was equivalent to the proliferation of aged T cells cultured with aged M phi. These results suggest that aging has differential effects on polyclonal and antigen-specific T cell proliferation and on polyclonal stimulation of T cells isolated from different lymphoid organs and from different strains of mice.