[Effectiveness of vaccination against influenza in the elderly].
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Biomedical subjects
Publications and source records attributed to B K Pedersen.
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The purpose of the study was to examine how memory (CD45RO) and naive (CD45RA) phenotypes of CD4+ and CD8+ T-cell subpopulations changed with respect to progression and duration of human immunodeficiency virus (HIV) infection. Forty-three HIV-seropositive (HIV+) subjects with known time for seroconversion were included in this cross-sectional study. They were divided into the following groups for comparison: persons with and without AIDS, persons who had seroconverted > 72 and < 72 months before entering the study, persons with or without previous severe primary infection, persons who had developed AIDS > 72 and <72 months before entering the study. Furthermore, the HIV+ group was compared with an HIV-seronegative (HIV-) age- and sex-matched group. There was no difference in the proportion of total naive relative to total memory cells between HIV+ and HIV- subjects, showing an equal loss of naive and memory CD4+ cells in this study. Moreover, there was no difference in the proportion of total naive relative to memory CD8+ cells, showing an equal increase in both subgroups of CD8+ cells in HIV+ subjects. However, HIV+ subjects who had experienced severe primary symptoms resembled the AIDS group regarding shift in the CD8 phenotype from naive to memory and by down-regulation of amounts of CD45RA protein. Furthermore, the results showed that during infection with HIV the amounts of both CD45RA and CD45RO markers on CD4+ cells and CD45RA on CD8+ cells were down-regulated, although with different kinetics.(ABSTRACT TRUNCATED AT 250 WORDS)
Cytotoxicity mediated by natural killer (NK) and lymphokine-activated killer (LAK) cells may be of significance in host defense against viral infections. This study included 347 patients infected with human immunodeficiency syndrome virus (HIV) type 1 and 110 controls. The NK cell activity, either unstimulated or stimulated with interferon-alpha (IFN-alpha) or interleukin-2 (IL-2), and the LAK cell activity were suppressed in patients, but the NK/LAK cell activity did not differ between patients with AIDS and patients without AIDS. However, the IFN-alpha-stimulated NK cell activity and LAK cell activity were reduced in patients with symptoms of HIV disease (CDCIV) when compared with asymptomatic patients (CDCII+III). When the data were analyzed by multiple linear regression, the percentage of CD4+ cells had a positive effect on these two parameters in patients without AIDS, whereas the percentage of CD4+ cells had no significant effect on unstimulated and IL-2-stimulated NK cell activity in these patients. In controls and AIDS patients, the percentage of CD4+ cells had no effect on NK/LAK cell activity in multiple linear models. The total number of CD16+ cells was low in patients compared to controls, whereas the percentages of CD16+, CD56+, and CD16+CD56+ were either normal or elevated. Therefore, the decrease in NK cell subpopulations did not contribute to the observed depression in NK/LAK cell activity in vitro. It is concluded that natural immunity is suppressed in HIV-seropositive patients primarily because of a qualitative defect of the NK/LAK cells. This qualitative defect includes a reduced responsiveness to IFN-alpha, which is progressive until the onset of symptoms, and possibly related to the loss of CD4+ cells.
Pulmonary diffusion capacity (DLCO) is reduced 2 h after various types of exercise, such as rowing, treadmill running, arm cranking and marathon running. The decrease in DLCO may involve alterations in the alveolar-capillary membrane as well as depletion of the central blood volume. We hypothesized that the reduction in DLCO might also be influenced by oxygen free radicals, acute phase proteins and endotoxin, which are also involved in the adult respiratory distress syndrome (ARDS). Ten competitive male oarsmen performed a 6 min 'all-out' ergometer row. Single breath DLCO was determined before and 2 h after rowing and venous blood samples were also obtained during the row. Absolute DLCO decreased by 11% (range 0-20%) 2 h after rowing, whereas the concentration of endotoxin did not change significantly and interleukin (IL)-1-alpha, IL-8 and tumour necrosis factor (TNF)-alpha were below the levels of detection before, during and 2 h after rowing. Oxygen free radicals were evaluated by oxidative modification of amino acids and DNA. Corrected for creatinine in urine voided 3 h post-exercise, the DNA repair product 8-oxo-7,8-dehydro-2-deoxyguanosine (8-oxodG) did not change significantly. The ratio of fluorescence due to dityrosine to that due to tryptophan in plasma proteins increased after exercise. This might reflect an effect of oxygen free radicals, but it might also indicate an altered relative composition of plasma proteins. These results suggest that the reduced pulmonary diffusion capacity following exercise is unrelated to factors typically associated with ARDS.
For the response of immunologically competent blood cells to exercise, the importance of afferent nerve impulses was evaluated. On separate days, seven males cycled in a recumbent position approximately 60% of maximal O2 uptake with and without sensory nerve blockade by lumbar epidural anesthesia. Blood samples were collected after 60 min of rest, 20 min of exercise, and 120 min postexercise. Subsequently, on each day, the subjects were exposed to 11.5% O2-88.5% N2 for 10 min. This was followed by 20 min of hypoxic exercise at the same work rate, and a final blood sample was obtained. The concentrations of lymphocytes expressing the cluster designation (CD) cell-surface antigens CD3, CD4, CD8, and CD14 became elevated during exercise, and these responses were enhanced by hypoxia (P < or = 0.01). The most pronounced changes were within the concentrations of CD16+ and CD56+ natural killer cells, which increased twofold during normoxic and fivefold during hypoxic exercise (P < or = 0.01). Sensory nerve blockade decreased the number of CD3+ and CD4+ cells and increased the percentage of CD16+ cells, independent of exercise and hypoxia (P < or = 0.05). Sensory nerve blockade caused minor enhancement in the increase of unstimulated natural killer cell activity during exercise (P = 0.07) and enhanced the interferon-alpha-stimulated activity at normoxia (P < or = 0.05), whereas no effect was detected at hypoxia. The results demonstrate that the responses of immunological competent cells to normoxic and hypoxic exercise are not abolished by blockade of nerve impulses from active muscle.
The effect of eccentric one-legged exercise on natural killer (NK) cell activity was studied in eight healthy males. To distinguish between local and systemic effects, blood samples were collected from veins in the exercising leg and resting arm. However, the results did not significantly differ between the leg and arm. To eliminate diurnal variations, the results were compared with a control group that did not exercise but had blood samples collected at the same time points. In the exercising group, plasma creatine kinase increased progressively during and up to 4 days after exercise. The percentage of CD16+ NK cells increased during exercise, which was paralleled by an increase in the NK cell activity per fixed number of blood mononuclear cells. The NK cell activity on a per NK cell basis did not change. The percentage of CD3+, CD4+, CD8+, CD19+, and CD14+ cells did not change significantly during exercise. The present study thus showed that eccentric exercise with a relatively small muscle mass (1 quadriceps femoris muscle) causes systemic effects on NK cells. It is suggested that the increase in plasma epinephrine during eccentric exercise is responsible for the observed increase in the percentage of CD16+ cells.
Glutamine increased the proliferative response and the lymphokine-activated killer cell activity of blood mononuclear cells isolated from normal healthy subjects (n = 6) in a dose-dependent manner, with optimum at 0.3-1.0 mM. The relative fraction of CD3+, CD4+, CD8+, CD14+, CD16+, and CD19+ cells was not changed by glutamine at a concentration of 0.6 mM, except in the phytohemagglutinin-stimulated proliferation experiment where the fraction of CD4+, and therefore CD3+ cells, increased. The natural killer cell activity was not influenced by glutamine. Human immunodeficiency virus (HIV)-seropositive subjects (n = 8) who performed concentric bicycle exercise for 1 h at 75% of maximal O2 consumption had an overall lower phytohemagglutinin-stimulated proliferative response, compared with the HIV-seronegative control group (n = 7). The proliferation during exercise was lower in both the HIV-seropositive and the HIV-seronegative group. Addition of glutamine in vitro did not normalize the lower proliferation in the HIV-seropositive group or the attenuated proliferation seen during exercise in both groups.
During exercise, leucocytes are recruited to the blood, and if muscle damage occurs the cytokine level is enhanced. After prolonged, intense exercise the number of lymphocytes in the blood is reduced, and the function of natural killer cells is suppressed; furthermore, secretory immunity is impaired. During this time of immunodepression, often referred to as 'the open window', the host may be more susceptible to micro-organisms bypassing the first line of defence. This is of interest to top athletes who perform frequent severe exercise. Clinical observations regarding an increased risk of infections in top athletes are compatible with this model. However, in those performing regular moderate exercise the immune system will often be temporarily enhanced and this will protect these individuals from infections.
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Natural killer cell activity against K562 target cells was measured during active disease (within 48 hours after symptom debut, day 0), and in remission stages (days 14 and 28) of 10 patients with recurrent aphthous ulceration. Ten healthy sex- and age-matched persons with a negative history of recurrent aphthous ulceration served as controls. Baseline, interferon-alpha- and interleukin-2-boosted natural killer cell activity was not significantly different between patients and controls at any of the three time periods. Furthermore, the percentages of peripheral CD16+, CD56+, and CD14+ cells were at no time significantly different between patients and controls. This study supports other investigations with respect to a systemic T-cell imbalance in which a decreased CD3+ and CD4+ fraction is encountered among patients with recurrent aphthous ulceration; however, the previously reported increase in the CD8+ subsets was not confirmed in the present study. Although no quantitative or nonspecific functional alterations of circulating peripheral natural killer cells were observed in patients with recurrent aphthous ulceration, this does not preclude NK cell involvement in the lesion sites. Furthermore, with recent studies that suggest a possible implication of varicella zoster virus or cytomegalovirus in recurrent aphthous ulceration, studies of varicella zoster virus and cytomegalovirus specific killer activity in this patient population are hereby encouraged.
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The effect of heavy short-term physical exercise on the levels of complement receptor type one (CR1, CD35) on erythrocytes, the concentrations of circulating immune complexes (IC), and the complement C3 split products C3c and C3d were examined in young healthy males. Fourteen untrained volunteers underwent a 60-min bicycle exercise test at 75% of maximal oxygen uptake (VO2max). Six of the volunteers were exercised twice with an interval of at least one month. Before the second bicycle test they received oral indomethacin. With an interval of at least 1 week, 6 also went through a 60-min back-muscle exercise at up to 30% of VO2max. Blood samples were collected before and during the last few minutes of exercise as well as 2 h and 24 h afterwards. The same parameters were examined once in 29 highly trained racing cyclists. There were no consistent or significant exercise-induced changes in the levels of erythrocyte CR1, circulating IC, C3c nor C3d as measured by an enzyme-linked immunosorbent assay, polyethylene glycol precipitation complement consumption method, and by intermediate gel rocket immunoelectrophoresis, respectively. Neither did these parameters differ from controls in the highly trained group. The results indicate that CR1 on erythrocytes, circulating immune complexes and complement cleavage products C3c and C3d in healthy subjects remain unaffected by short-term heavy physical activity and training.
The present study was designed to examine the effect of physical exercise on production of interleukin-1 (IL-1), interleukin-6 (IL-6), tumour necrosis factor-alpha (TNF-alpha), interleukin-2 (IL-2) and interferon-gamma (IFN-gamma). Ten young, healthy volunteers underwent 60-min bicycle exercise at 75% of maximal oxygen uptake (VO2max). Blood samples were collected before and during the last minutes of exercise, as well as 2 h and 24 h later. Blood mononuclear cells (BMNC) were stimulated in vitro with either bacterial lipopolysaccharide or phytohaemagglutinin, and the supernatants were tested for the above-mentioned cytokines using bioassays as well as ELISA techniques. The production of IL-6 increased significantly 2 h after exercise, furthermore the production of IL-1 alpha and IL-1 beta was enhanced, although only borderline significant. TNF-alpha, IL-2 and IFN-gamma did not fluctuate in relation to exercise. The increased amounts of IL-1 and IL-6 in the supernatants generated from a fixed number of BMNC are most likely explained by the increased percentage and absolute number of blood monocytes 2 h after exercise. IL-2 and IFN-gamma are mainly produced by CD4+ and CD16+ cells. During exercise the CD4+ subset decreases, while the CD16+ subset increases. The finding of unchanged production of IL-2 and IFN-gamma was therefore expected.
This review deals with the effect of acute physical exercise and training status on different components of the immune system. Predominantly studies in humans are mentioned. In relation to acute physical exercise (75% of VO2max, 1 hour) the leukocyte concentration increased; following exercise the neutrophils increased fourfold. The lymhphocyte concentration increased during and decreased following exercise. The percentage of CD3+ cells (pan T cells) declined during exercise, mainly due to a fall in the %CD4+ cells. The %CD16+ cells (NK cells) increased two-fold and returned to prevalue two hours after exercise. The %CD20+ cells (B cells) did not change in relation to exercise, whereas the %CD14+ cells (monocytes) increased two to threefold following exercise. The NK cell activity increased during but decreased following exercise. These increases were due to recruitment of NK cells with a high IL-2 response capacity, whereas the decreased NK activity post-exercise was due to downregulation by prostaglandins released by the elevated concentration of monocytes. During severe, moderate as well as light exercise, the NK cell activity increased, but the post-exercise suppression of the NK cell function was found only following severe exercise, and not after moderate or light exercise, furthermore, only following severe exercise, an increased monocyte concentration was demonstrated. The IL-2-stimulated lymphocyte proliferative response increased due to stimulation of CD16+ cells and did not reflect expression of IL-2 receptors.
This work was designed to test the hypothesis that elevations in body temperature of humans induce immunostimulation. Eight healthy volunteers were immersed in a water bath (water temperature 39.5 degrees C) for 2 h, during which their rectal temperature rose to 39.5 degrees C. On a later day they served as their own controls, being immersed into thermoneutral water (34.5 degrees C) for 2 h. Blood samples were collected before immersion, at body temperatures of 38 degree C, 39 degree C and 39.5 degree C, and 2 h after water immersion. The interleukin-2 (IL-2) enhanced natural killer (NK) cell activity (lysis per fixed number of mononuclear cells), as well as the proportion and total number of NK cells (CD16+ cells), increased significantly during hyperthermia compared with control values. The lymphocyte proliferative responses did not differ significantly between hyperthermia and thermoneutral conditions. The proportion of pan-T (CD3+) cells was maximally depressed 2 h after water immersion. The decreased proportion of CD3+ cells was mainly due to a decreased percentage of CD4+ cells (not significant). The proportion of B cells (CD19+ cells) did not fluctuate significantly, while a marked and significant increase in monocyte proportion (CD14+ cells) was found 2 h after hyperthermia. Two hours after hot water immersion the lymphocyte concentration declined while the neutrophil and monocyte concentrations were augmented. Induced hyperthermia causes significantly increased serum cortisol, plasma norepinephrine and plasma epinephrine concentrations compared to controls. It is possible that the altered immune functions induced by elevated body temperature can be ascribed to altered composition and function of blood mononuclear cells induced by elevated levels of stress hormones.
The present study was designed to test the hypothesis that the changes in natural killer (NK) cell activity in response to physical exercise were mediated by increased epinephrine concentrations. Eight healthy volunteers 1) exercised on a bicycle ergometer (60 min, 75% of maximal O2 uptake) and 2) on a later day were given epinephrine as an intravenous infusion to obtain plasma epinephrine concentrations comparable with those seen during exercise. Blood samples were collected in the basal state, during the last minutes of exercise or epinephrine infusion, and 2 h later. The NK cell activity (lysis/fixed number of mononuclear cells) increased during exercise and epinephrine infusion and dropped below basal levels 2 h afterward. The increased NK cell activity during exercise and the epinephrine infusion resulted from an increased concentration of NK (CD16+) cells in the peripheral blood. On the other hand, the decreased NK cell activity demonstrated 2 h after exercise and epinephrine infusion did not simply reflect preferential removal of NK cells from the blood, because the proportion of CD16+ cells was normalized. On the basis of the finding that indomethacin abolished the suppressed NK cell activity in vitro and the demonstration of a twofold increase in the proportion of monocytes (CD14+ cells) 2 h after exercise and epinephrine infusion, we suggest that, after stress, prostaglandins released by monocytes are responsible for downregulation of NK cell function. Our findings support the hypothesis that increased plasma epinephrine during physical stress causes a redistribution of mononuclear subpopulations that results in altered function of NK cells.
In vitro studies have shown that anti-malarial drugs suppress immunity. In this study, the effects of chloroquine and proguanil (Paludrine) on the cellular and humoral immune system were measured by two in vivo methods: 1) cell-mediated immunity (delayed cutaneous hypersensitivity) i.e., skin tests with seven delayed-type common antigens (Multitest) and 2) humoral immunity by measurement of specific antibody response to vaccination. Sixty healthy young individuals were randomized into four groups and given 1) no treatment (controls), 2) chloroquine diphosphate (500 mg/week), 3) chloroquine diphosphate (1,000 mg/week), or 4) proguanil hydrochloride (200 mg/day) for six weeks. Skin testing was performed on days 0 and 28. Vaccinations with diphtheria, tetanus, polio, and pneumococcal polysaccharide antigen vaccines were performed on day 28, and the presence of specific antibodies was determined on days 0, 28, and 42. The skin tests induced a significant increase in skin reactive areas from day 0 to day 28 in all groups. Furthermore, the skin test induced an increase in the level of specific IgG for diphtheria and tetanus, but had no effect on antibodies to antigens not included in the skin test. The results showed that there were no significant differences among the four groups regarding skin test areas and increases in antibody titers following vaccination. Therefore, it is concluded that in healthy persons, six weeks intake of chloroquine, even in double doses, or proguanil in chemoprophylactic dosages, does not induce any detectable suppression of delayed-type hypersensitivity or vaccination responses to diphtheria, tetanus, polio, or pneumococcal polysaccharide antigens.