Changes In Natural Killer Activity Research Articles

Restoration of natural killer cell activity by pegylated interferon‐alpha/ribavirin therapy in chronic hepatitis C patient

The combination therapy of pegylated interferon-α and ribavirin (PEG IFN/RBV) is one of the effective treatments for chronic hepatitis C (CHC) patients. Natural killer (NK)-cell activity was reported to be impaired in patients with hepatitis C virus (HCV). The aim of this study was to examine whether PEG IFN/RBV therapy could restore NK activity in CHC patients. In 19 CHC patients, PEG IFN/RBV therapy was performed. Just before (0M), at 3 months of the therapy (3M) and at 6 months after completion of the therapy (6M), NK activity and the frequency of NK cells, CD56(dim) NK cells and CD56(bright) NK cells in peripheral blood was estimated by creatinine release assay and flow cytometry. Statistical analysis was performed by anova and Mann-Whitney U-test. anova showed that NK activity significantly improved at 6M (vs 0M, P < 0.05) in the patients studied and in the patients with sustained virological response (SVR). It also showed that frequency of CD56(bright) NK cells was significantly increased at 6M (vs 0M, P < 0.05) in the patients studied and in the SVR group. However, no significant change in NK activity and frequency of CD56(bright) NK cells were detected in non-SVR group. Furthermore, NK activity ratio (6M/0M) in the SVR group was revealed to be higher compared with that in the non-SVR group by analysis using Mann-Whitney U-test (P < 0.05). PEG IFN/RBV therapy in CHC patients could improve NK activity by increasing the frequency of CD56(bright) NK cells in SVR patients. Our study also revealed that eradication of HCV could restore NK-cell activity.

Neuroimmune mechanisms of opioid-mediated conditioned immunomodulation

Morphine administration elicits pronounced effects on the immune system, including decreases in natural killer (NK) cell activity and lymphocyte mitogenic responsiveness. These immune alterations can become conditioned to environmental stimuli that predict morphine as a result of Pavlovian conditioning processes. Prior work in our laboratory has shown that acute morphine exposure produces dopamine-dependent reductions of NK cell activity that are mediated peripherally by neuropeptide Y Y 1 receptors. The present study examined the involvement of dopamine D 1 and neuropeptide Y Y 1 receptors in the conditioned immunomodulatory effects of morphine. Rats received two conditioning sessions during which an injection of morphine was paired with a distinctive environment which served as the conditioned stimulus (CS). The results show that systemic administration of the D 1 antagonist SCH-23390 prior to CS re-exposure prevented the conditioned suppression of splenic NK activity but did not alter conditioned decreases in mitogen-induced lymphocyte proliferation. Furthermore, bilateral microinjections of SCH-23390 directly into the nucleus accumbens shell fully blocked conditioned changes in NK activity. In a subsequent manipulation, subcutaneous injection of the Y 1 receptor antagonist BIBP3226 prior to CS re-exposure was also shown to prevent conditioned effects on NK activity. Collectively, these findings provide evidence that the nucleus accumbens shell plays an important role in conditioned immunomodulation and further suggest that the conditioned and unconditioned immunomodulatory effects of opioids involve similar receptor mechanisms.

Immune markers and ornithine decarboxylase activity among electric utility workers.

The effects of a 60-Hz magnetic field (MF) exposure on white blood cell ornithine decarboxylase (ODC) activity, natural killer (NK) cell activity, lymphocyte phenotypes, and differential cell counts were studied among 60 electric utility workers. Personal MF exposure monitoring over 3 consecutive workdays was followed by collection of a peripheral blood sample. There were no MF-related changes in NK activity or the number of circulating neutrophils, eosinophils, basophils, or T-lymphocytes (CD4, CD8, CD4:CD8 ratio). MF exposure intensity was associated with decreased ODC activity (P<0.01) and lower NK cell counts (P=0.04). Melatonin production, which stimulates the immune system, was quantified on the night preceding immune marker determinations. Exposure-related reductions in ODC activity, NK and B cells, and monocytes were strongest among workers with reduced melatonin production. The biological significance or long-term health consequences associated with these changes are not known.

Natural killer activity and its changes among participants in a smoking cessation intervention program--a prospective pilot study of 6 months' duration.

We examined the effect of smoking cessation on natural killer (NK) activity of peripheral blood lymphocytes in terms of a prospective study of 27 Japanese subjects who participated in a smoking cessation intervention program. This program was delivered by means of group-counseling offering 7 sessions of about 2 hours over 6 months to help smokers to discontinue the habit. Thirteen subjects ceased smoking (quitters), while 14 continued to smoke (cigarette smokers). NK activity before the intervention was correlated positively with age (correlation coefficient=0.46, P<0.05). NK activity remained almost constant among quitters, comparing the activity before and after the intervention, while it decreased among cigarette smokers although it was not statistically significant. In the subgroup analysis, NK activity increased among those aged less than 65 years, or urine cotinine levels over 800 ng/ml before the intervention, especially among quitters, but there were no statistical significances. Multiple regression analysis showed changes in NK activity were correlated significantly only with age (standard regression coefficient=-0.44, P<0.05). These findings suggest that smoking cessation intervention programs might have been more effective for younger than elder subjects in consideration of NK activity.

Time-of-day effects on response of natural killer cells to acute stress in men and women.

Diurnal influences on natural killer (NK) cell changes to acute stress were assessed in 21 men and 21 women assigned to either an acute stress (mental arithmetic) or control task condition. Sessions began at either 8 a.m. or 2 p.m. Number of NK (CD3-CD56+) cells and NK activity were measured at baseline, during the 5-min task, and 60 and 90 min after the task. Both morning and afternoon stress participants had elevated NK cell numbers during the task. After the task, number of NK cells decreased in morning stress participants but remained significantly above baseline levels 60 and 90 min posttask. NK cell numbers in afternoon stress participants decreased to below baseline levels 60 and 90 min after the task. Changes in NK activity were driven primarily by diurnal influences. NK activity increased in all morning participants and stayed increased 60 and 90 min posttask. NK activity of all afternoon participants also increased during the task but dropped below baseline 60 and 90 min later. Greater increases in NK levels and activity during the task were associated with greater heart rate changes.

Depression and immunity: clinical factors and therapeutic course

While many reports describe associations between depressive disorders and altered immunity, findings have not been fully consistent. Diagnostic subtype, demographic factors such as age and gender, medical characteristics, and the immune measures selected for assessment may have contributed to the heterogeneous findings. In a study of 21 medically healthy young adults with major depression, we found, consistent with previous reports, evidence of increased lymphocyte activation to mitogen challenge and decreased natural killer (NK) cell numbers and function during acute depression. Fifteen subjects were followed longitudinally. T, CD4 +, CD29 +, and CD45RA + lymphocytes and T-cell mitogen responses decreased significantly ( P < 0.05) during 6 weeks of pharmacotherapy and concurrent clinical improvement. There was no change in NK activity or CD56 + cells. The longitudinal effects appeared unrelated to tricyclic antidepressant levels. Changes in the immune system with short-term clinical improvement in depressed patients are not uniform providing further evidence that several mechanisms are involved in the altered immunity associated with clinical depression.

Effect of Endogenous Cortisol Levels on Natural Killer Cell Activity in Healthy Humans

The aim of this study was to examine the effects of increasing and decreasing endogenous cortisol levels on natural killer (NK) cell activityin vivo.Normal healthy volunteers participated in the following studies: baseline (n= 27), metyrapone challenge test (n= 10), dexamethasone suppression test (n= 10), and adrenocorticotropic hormone (ACTH) stimulation test (n= 8). Each subject served as his own control for each study. Each subject was tested for NK activity and plasma cortisol levels at 9a.m., just before the challenge drug administration, and at 10a.m., except for the dexamethasone study, in which only the 9a.m.blood was drawn, 10 h after the dexamethasone administration. On the baseline study day, a significant decrease in plasma cortisol levels was found from 9 to 10a.m.(p< .02) along with a significant increase in NK activity (p< .001). On the metyrapone test day, plasma cortisol levels at 10a.m.were significantly reduced (p< .005) as expected, while NK activity at the same time point was not affected and was increased to an extent equivalent to the baseline study day. On the dexamethasone test day, plasma cortisol concentrations were significantly decreased (p< .0001) as compared to the same time point on the baseline day, without any significant change in the NK activity. On the ACTH test day, plasma cortisol rose significantly at 10a.m.(p< .02), with no change in NK activity. We conclude that plasma cortisol alone has no significant effect on NK activityin vivo.

Life events, frontal electroencephalogram laterality, and functional immune status after acute psychological stressors in adolescents.

Past studies have found that environmental stress affects cellular immune function and that extensive variability exists in the magnitude and direction of stress-induced immune changes. Past research also suggests that individuals with greater right, relative to left, resting frontal electroencephalogram (EEG) activation perceive environmental stress as more aversive and have lower baseline cellular immune function. In this study, we examined environmental stressors, resting frontal EEG laterality, and immune responses to short-term psychological stressors in adolescent boys. A sample of twenty-four 14-16 year old right-handed boys underwent a recording of resting EEG and collections of blood taken before and after a laboratory protocol designed to induce psychological stress. Blood samples were used to measure changes in mitogen lymphoproliferative responses, natural killer (NK) cell activity, and T-cell phenotypic subsets. Life events were measured using self-report questionnaires. Life events and frontal laterality showed a first order interaction in predicting changes in lymphocyte proliferation to tetanus toxoid (R2 increment = .26, p < .01) and pokeweed mitogen (R2 increment = .25, p < .02). The interaction also predicted changes in NK activity (R2 increment = .24, p < .02). Changes in lymphocyte proliferation and NK activity were associated with negative life events only among individuals with greater left frontal cortical activation. Our results suggest that recent psychosocial stress and individual differences in resting frontal cortical activation are together linked to immunologic responses to acute psychological stressors.

Extension of the 4-week safety study for detecting immune system impairment appears not necessary: example of cyclosporin A in rats

A 4-week study was conducted to shed light on the question of whether compounds impairing immune homeostasis may escape the standard safety testing. Wistar rats were orally treated with cyclosporin A at dosages of 0 (control: olive oil), 1, 5 or 25 mg/kg/day. Ten rats/sex/group (study segment 1) were not immunized while six other rats/sex/group (study segment 2) were immunized 4 days before killing to perform a plaque forming cell (PFC) assay. All rats were subjected to routine safety evaluations (OECD guideline 407) and determination of IgM and IgG serum levels. Other immune parameters were evaluated using cells from spleen and mesenteric lymph nodes (segment 1). Effects on safety parameters were similar for immunized and non-immunized rats. A slight decrease of body weight gain (males, 25 mg/kg) accompanied slight clinical chemical and histomorphologic evidence of renal tubulotoxicity. Changes in safety parameters indicative of immune system alterations were: increased thymic corticomedullary ratio (≥5 mg/kg) and (25 mg/kg) minimal lymphopenia, low thymus weight, thymic cortical lymphocytolysis and low lymphoid cellularity of spleen and lymph nodes. They were associated with (males at ≥ 1 mg/kg) dose-related decreases of T-cell receptor + and CD4 + cells and increases of CDS + cells, and decreased PFC (≥5 mg/kg) and lymphoproliferative responses to mitogens and alloantigens (25 mg/kg). There were no changes in natural killer activity. The conventional assay identified the drug as a potential immunomodulator. Specific immune assays (phenotyping, PFC) improved the threshold of detection. These results did not support the incorporation of specific immune tests in the standard 4-week study protocol.

Natural Killer Cells Inhibit the Development of Autoantibody Production in (C57BL/6 × DBA/2) F1 Hybrid Mice Injected with DBA/2 Spleen Cells

We investigated the role of natural killer (NK) cells in the development of autoantibody production in which (C57BL/6 × DBA/2) F1 (BDF1) hybrid mice were injected intravenously with spleen cells (SC) from parental DBA/2 mice (treated BDF1 mice). Treated BDF1 mice began to show an increase in serum anti-dsDNA antibody 2 weeks after injection, while the NK activity of their SC transiently increased initially in the first 1 to 2 weeks after injection, but subsequently decreased dramatically. Flow cytometric analysis suggested that this sequential change in NK activity correlated with the absolute number of host-derived NK1.11 cells in SC from treated BDF1 mice. We demonstrated that the level of anti-dsDNA in serum is directly influenced by the level of NK activity in treated BDF1 mice. Depletion of NK cells by administration of anti-NK1.1 mAb accelerated the development of autoantibody production, whereas augmentation of NK activity by administration of poly-(I:C) inhibited the development of autoantibody production. This inhibitory effect of poly(I:C) was abolished by prior depletion of NK cells. Interestingly, suppression of autoantibody production was seen only when poly(I:C) was administrated within 1 week after injection of parental SC. Last, we demonstrate that adoptive transfer of interleukin-2 (IL-2)-activated NK cells had a protective effect against the development of autoantibody production. These findings imply that NK cells may have a protective role in lupus-like disease especially in its early stage. In addition, it opens up the possibility that adoptive immunotherapy with IL-2-activated NK cells can delay or even prevent the development of autoimmune disease.

Role of human natural killer cells in health and disease.

Natural killer (NK) cells, the CD3- CD56+ CD16+ subset of peripheral blood lymphocytes, have long been known to be involved in non-major histocompatibility complex-restricted natural immunity to virally infected and malignant target cells. The association of abnormalities in NK cell numbers or functions with a broad spectrum of human diseases has been more clearly defined in recent years as a result of the improved knowledge of NK cell physiology and advances in monitoring of NK cell functions in health and disease. The ability to reliably measure changes in NK activity and/or numbers during the course of disease or response to treatment has focused attention on the role of the NK cell in disease pathogenesis. The improved understanding of NK cell deficiency in disease has opened a way for therapies specifically designed to improve NK cell function. The therapeutic use of biologic response modifiers capable of augmenting NK cell activity in vivo and of adoptive transfer of highly enriched, activated autologous NK cells in diseases such as cancer and AIDS is being evaluated. The importance of NK cells in health and the consequences of NK cell deficiency or excess are likely to be more extensively monitored in the future.

Changes in Natural Killer Activity and Antibody-Dependent Cellular Cytotoxicity of Murine Axillary Nodes, Spleen and Thymus with Acute Physical Exercise or Training. Variations with Sex and Ageing

Changes in Natural Killer Activity and Antibody-Dependent Cellular Cytotoxicity of Murine Axillary Nodes, Spleen and Thymus with Acute Physical Exercise or Training. Variations with Sex and Ageing

Regulation of NK cell activity and the level of the intracellular cAMP in human peripheral blood lymphocytes by Met-enkephalin.

The effect of Met-enkephalin on natural killer (NK) activity and on intracellular cyclic adenosine monophosphate (cAMP) level in human peripheral blood lymphocytes was measured 1/4, 1, 2, and 24 h after incubation. Concentrations of Met-enkephalin ranged from 10(-12) to 10(-8) M. Cyclic changes in NK activity and in the intracellular cAMP level after treatment with Met-enkephalin were observed. Kinetics of changes caused by high (10(-9), 10(-8) M) and low concentrations (10(-12), 10(-11), 10(-10) M) of Met-enkephalin differed from each other. Early, nearly threefold increase in the level of intracellular cAMP was found 15 min after treating peripheral blood lymphocytes with 10(-12) M Met-enkephalin. By contrast, a nearly 75% decrease of intracellular cAMP level was found 2 h after treatment with 10(-9) M Met-enkephalin. Generally, early intensive changes in the cAMP level in peripheral blood lymphocytes, induced by Met-enkephalin, were followed by delayed, subtle changes in NK cell activity in the opposite direction.

Supplemental growth hormone increases the tumor cytotoxic activity of natural killer cells in healthy adults with normal growth hormone secretion

Using double-blind, placebo-controlled procedures, the effects of methionyl-human growth hormone (met-hGH) on the tumor cytotoxic activity of natural killer (NK) cells were studied in seven healthy adults using a repeated measures experiment. Subjects were assigned at random to either a placebo (bacteriostatic water) treatment condition or a met-hGH (16.0 mg/wk of Protropin) treatment condition, then crossed-over to the alternative treatment. Treatments were delivered on alternate days (3 d/wk) for 6 weeks. Without bias from the met-hGH treatment, there was no evidence for GH hyposecretion as measured by the peak circulating GH response to exercise stimulation (14.1 ± 3.1 ng/mL) or insulin-like growth factor (IGF-I) levels (0.82 ± 0.09 U/mL). When compared with placebo, met-hGH induced a significant overall increase in the percent specific lysis (%SL) of K562 tumor target cells (placebo 22.2 ± 1.7 v met-hGH 28.5 ± 2.1 %SL; P = .008). NK activity was increased within the first week of treatment and this level was maintained throughout the remaining period of supplementation. There was a trend ( P = .057) for the met-hGH-induced percent change in NK activity (NK%) to be inversely related to placebo IGF-I levels ( r = −.761), while there were significant positive correlations between NK% and the met-hGH-induced percent changes in IGF-I ( r = .727; P = .035), the fat-free mass (FFM)/fat mass (FM) ratio derived by hydrodensitometry ( r = .792; P = .012), and the endogenous GH response to exercise ( r = .469; P = .034). We conclude that supplemental GH increases NK activity in healthy adults with normal GH secretion and that this effect is interrelated to the body composition and IGF-I responses to the hormone. Since these findings were observed in the absence of GH hyposecretion, exogenous GH might be of benefit in states in which the normal anabolic processes in vivo are insufficient to overcome the taxing influence of disease and/or disuse.

Natural killer cell activity: age, estrous- and circadian-stage dependence and inverse correlation with metastatic potential.

The timing within the estrous cycle of surgical removal of a transplanted murine mammary tumor profoundly influences the frequency of pulmonary metastases. We investigated the potential role of the immune response in this phenomenon by measuring splenic natural killer (NK) cell activity and interleukin-2 (IL-2) production in syngeneic tumor-free mice of two age groups at each of two circadian times and in each of four estrous stages. Estrous stage was determined by assessment of vaginal smear cellularity immediately prior to killing and spleen harvest. In a single-cell splenocyte preparation, NK cytotoxicity against a standard tumor cell target was assessed using a radiolabeled chromium release assay while IL-2 activity was determined in a bioassay utilizing the IL-2-dependent CTLL-2 cell line. Mice from the younger group were found to have eight-fold higher NK activity and 35% greater IL-2 production. After normalization of NK and IL-2 values for age, a highly statistically significant difference in NK activity was found among the four estrous and between the two circadian stages of sacrifice. NK activity was greater during the daily resting span across every estrous stage. IL-2 values were highest in diestrus and proestrus when sampled in the light span and in estrus-metestrus when sampled in the dark. The stages within the fertility cycle associated with lowest metastatic potential (proestrus/estrus) correspond precisely with those of highest splenocyte NK activity. These results indicate that an important component of the cellular immune response varies rhythmically both during the fertility and circadian cycles of the host. The rhythmic changes in NK activity may be in part responsible for the similarly rhythmic frequency of postsurgical metastatic dissemination.

Effects of orally administered retinol on natural killer cell activity in wild type BALB/c and congenitally athymic BALB/c mice.

Retinoids have been shown to inhibit the growth and development of neoplastic cells in many systems. One mechanism of action may be through activation of the immune system, specifically natural killer (NK) cell activity. The effect of retinol on NK cell cytotoxicity was examined in three groups of mice: BALB/c (wild-type), BALB/c nu/nu (athymic), and BALB/c nu/nu previously injected with human tumor cells. In untreated mice, NK activity was highest in athymic mice without tumors and lowest in wild-type mice, although serum and liver retinol concentrations were identical in all three groups. In mice fed graded, nontoxic doses of retinol daily for 3 weeks, serum retinol levels in all three groups exhibited a sharp peak and decline following daily bolus retinol administration. Retinol stores in the livers showed a dose-dependent increase in all treated animals. However, NK cell activity, differed for each group. Athymic mice without tumors exhibited no change in NK activity as a result of retinol treatment. Athymic mice with tumors had NK levels that tended to increase with increasing retinol doses, but these changes were not statistically significant. Wild-type mice, on the other hand, demonstrated significantly higher NK levels after treatment with retinol doses of 300 and 600 micrograms/day. In subsequent time course experiments, there was a peak in NK activity 1 h following bolus retinol administration similar to the peak seen in serum retinol concentrations, suggesting either an acute activation or recruitment of cytotoxic cells. Retinol thus appears to increase NK activity in wild-type BALB/c mice, and this activity may be an important component of its antineoplastic activity.

Prospective study of natural cytotoxicity in peripheral blood of patients with nonlymphoid solid malignancies

Natural killer (NK) cells have been implicated as an initial immunosurveillance mechanism for carcinogenesis in humans. Work in the murine system as well as the findings of depressed NK activity in patients with advanced malignancies and the discovery of increased incidences of cancer in humans congenitally deficient in NK ability have supported this. Few prospective studies have demonstrated a prognostic change in NK activity with respect to malignant disease course. In 32 healthy donors, NK activity against K562 was determined. No race or sex difference existed with respect to NK cell function. Esophageal (5), bronchogenic (3), breast (3), cervical (3), and endometrial (1) cancer patients who had received no prior chemotherapy were compared to controls. All patients subsequently received radiotherapy. Prior to such treatment NK activity could not be associated with stage of malignancy. Of the 15 patients studied, 11 were sequentially followed. Five of eight patients with stable or improving clinical courses as assessed by weight and Karnofsky scores were found to have increasing NK activity. Two of three patients with poor clinical courses presented with subnormal killing which never rose to normal while the third declined to subnormal before expiring. Esophageal, cervical, and endometrial carcinoma patients all presented with low or subnormal NK activity. Of these, only cervical and endometrial cancer patients exhibited an increase to normal levels.

Effect of isoprinosine on natural killer cell activity of blood mononuclear cells in vitro and in vivo

Addition of isoprinosine to cultures of blood mononuclear cells was shown to inhibit natural killer (NK) cell activity against the K562 myeloid cells and melanoma cells. This appeared to be due to inhibitory influences of monocytes in that after removal of adherent cells isoprinosine appeared to stimulate NK activity. Similar effects were noted on T cells separated by E rosette procedures. Administration of isoprinosine in vivo had variable effects on NK activity during drug administration but there was a significant increases in NK activity 3 days after cessation of the drug. These changes in NK activity may reflect different threshold levels of the drug on suppressor and NK cell populations and the relative proportions of different lymphocyte populations in individual subjects. Further studies with a wider range of drug doses and more frequent monitoring of responses are required to further evaluate the effect of isoprinosine on NK activity.

Depression of natural killer cytotoxicity after in vivo administration of recombinant leukocyte interferon.

One hundred thirty-four patients with a variety of malignancies were treated in two phase I clinical trials of recombinant leukocyte A interferon (IFL-rA) produced by recombinant DNA methodology. IFL-rA was given by intra-muscular injection either twice daily or three times weekly for 28 days. Extensive monitoring of natural killer (NK) cell cytotoxicity was done on these patients with rigorously standardized assays and determination of the inherent variability of NK function for each individual. Interferon, as used in these two treatment regimens, failed to produce an appreciable increase in NK activity; in the majority of patients, there was no significant change in NK activity from the pretreatment baseline levels. An unexpected finding was the depression of NK activity in 30% of the patients. The data have been analyzed in terms of their possible relationship to dose and schedules of IFL-rA administration and to antitumor response.

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Natural killer (NK) cytotoxicity was assessed against K562 targets in 14 melanoma patients who received daily im doses of human leukocyte interferon (IFN) for 42 consecutive days. The most common pattern of NK activity was a decline from pretreatment levels 1 day after initiation of treatment, followed by increasing cytotoxicity with peak activity at day 7 and a subsequent gradual decline to pretreatment levels during the remaining weeks of treatment. This pattern was particularly apparent in patients who received 3 x 10(6) or 9 x 10(6) U IFN/day, while patients who received 1 X 10(6) U IFN/day tended to lack the decline at day 1 and maintained the elevated NK activity past day 7. Changes in NK activity could not be related to changes in absolute lymphocyte counts; to proportions of cells bearing membrane receptors for erythrocyte-antibody-complement, of cells bearing FC gamma receptor; or to clinical response to IFN.