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Immunological abnormalities in rats with adjuvant-induced arthritis--II. Effect of antiarthritic therapy on immune function in relation to disease development.

The effects of the experimental immunomodulatory agent tilomisole (Wy-18,251; (3-(p-chlorophenyl) thiazolo [3,2-a]benzimidazole-2-acetic acid) on disease development and immune function in rats with adjuvant-induced arthritis was assessed in comparison with indomethacin and levamisole. Daily p.o. administration of tilomisole (100-200 mg/kg/day) to M. butyricum-injected rats significantly reduced both edema and bone erosion in the uninjected paw. Moreover, tilomisole treatment restored to normal the diminished Con A-induced proliferative response and IL 2 synthesis observed in spleen cells from arthritic rats, but had no effect on macrophage IL 1 production. In contrast, levamisole treatment (25 mg/kg/day) of arthritic rats improved splenic immune function but did not influence paw edema or bone erosion. Conversely, indomethacin (1 mg/kg/day) significantly reduced paw edema and bone erosion but did not improve the deficient proliferative response or IL 2 synthesis by "arthritic" spleen cells. These results indicate that tilomisole possesses combined antiinflammatory and immunomodulatory activity in adjuvant-arthritic rats which is distinctly different from the effects of either indomethacin or levamisole. Moreover, these data suggest that tilomisole has potential disease-modifying activity in arthritis, which is currently being more closely examined in clinical trials.

Animals↗

Chronic exposure to aldicarb-contaminated groundwater and human immune function.

Aldicarb, a carbamate pesticide, has been a known groundwater contaminant in Wisconsin since 1981. To assess the effects of chronic ingestion of low-level aldicarb-contaminated groundwater (less than 61 ppb) on the immune function of humans, we identified 50 women, ages 18 to 70, with no known underlying reason for immunodysfunction. Twenty-three of these women (exposed group) consumed groundwater with detectable levels of aldicarb, and 27 (unexposed group) consumed water from a source with no detectable levels of aldicarb. Data were collected on each woman's health status, immune function, and fluid intake. Exposed women as compared with unexposed women showed an elevated stimulation assay response to the antigen Candida (P less than 0.02, t test). The exposed group had increased numbers of T8 cells (P less than 0.05, t test), an increased percentage of total lymphocytes as T8 cells (P less than 0.02, t test), and a decreased ratio of T4:T8 cells (P less than 0.02, t test). Our results suggest an association between consumption of aldicarb-contaminated groundwater and abnormalities in T-cell subsets in women with otherwise intact immune systems.

Adolescent↗

Immune function of young adult mice following in utero exposure to cyclophosphamide.

Long-lasting organic damage has been reported following in utero exposure to certain environmental or therapeutic agents. The sensitivity of the developing immune system to chemical insult during organogenesis or histogenesis was evaluated in mice employing the known immunosuppressive agent cyclophosphamide (CY). Experiments were conducted employing one of the following treatment regimens: (1) 1 microgram/g X d intravenously on d 9-12 or 14-17 of gestation; (2) 5 micrograms/g intravenously on 12 of gestation; (3) 1, 2.5, or 5 micrograms/g X d intraperitoneally on d 12 of gestation; or (4) 5, 10, or 20 micrograms/g intraperitoneally on d 17 of gestation. There were no surviving pups born to mothers administered CY by schedule 2; otherwise, numbers of surviving offspring were not affected by drug treatment, and no gross terata were observed. Employing this variety of exposure protocols, consistent enhancement or suppression of cell-mediated or humoral immune function was not observed in offspring of treated dams. Reduced body weight in 5- and 8-wk-old progeny was noted after exposure to 20 micrograms/g on gestational d 17. Increased in vitro B-lymphocyte blastogenic response to lipopolysaccharide occurred in 5-wk-old animals, and production of antibody to sheep erythrocytes was increased in 8-wk-old offspring exposed to CY at 20 micrograms/g on d 17 of gestation. The T-lymphocyte parameters were relatively unaffected by in utero exposure to CY, suggesting either that cell-mediated immune function was not affected by treatment or that homeostasis was restored prior to immunologic evaluation of offspring.

Animals↗

Effects of recombinant bovine interferons-alpha and -gamma on some in vitro immune functions of bovine intraepithelial and lamina propria leukocytes.

The effects of recombinant bacteria-derived bovine interferon-alpha I1 (rBoIFN-alpha I1) and -gamma (rBoIFN-gamma) on some in vitro immune functions of bovine intestinal leukocytes were studied. The proliferative response of intraepithelial leukocytes (IEL) to concanavalin A (Con A) was significantly inhibited by the addition of 5-1,000 U/ml of either IFN type. In contrast, addition of rBoIFN-alpha I1 to lamina propria leukocytes (LPL) from the same animal, showed significant inhibition only above 500 U/ml, whereas rBoIFN-gamma revealed significant enhancement when added as low as 50 U/ml. The concentration of mitogen and the time of incubation were both critical factors in determining the outcome of IFN-leukocyte interactions. While both IFN types could inhibit DNA synthesis of both leukocyte cultures at suboptimal (0.5 microgram/ml) Con A concentration throughout the time of incubation, their modulatory activities varied significantly at optimal (5.0 micrograms/ml) and supraoptimal (50.0 micrograms/ml) Con A concentrations. Preexposure of cells to IFNs or prestimulation with Con A did not significantly change the kinetics of IFNs with both leukocyte cultures. Pretreatment of leukocyte cultures with either IFN type for 18 h significantly enhanced the expression of MHC surface antigens. These data demonstrate that purified IFNs produced by recombinant DNA technology can significantly alter some in vitro immune functions of cells other than circulating leukocytes and that different IFNs have different capabilities to alter leukocyte functions.

Animals↗

Effects of cis-9, trans-11 and trans-10, cis-12 conjugated linoleic acid (CLA) isomers on immune function in healthy men.

OBJECTIVES: To study the effects of two different mixtures of the main conjugated linoleic acid (CLA) isomers cis-9, trans-11 CLA and trans-10, cis-12 CLA on human immune function. DESIGN: Double-blind, randomized, parallel, reference-controlled intervention study. SUBJECTS AND INTERVENTION: Seventy-one healthy males aged 31-69 y received one of the following treatments: (1). mixture of 50% c9,t11 CLA and 50% t10,c12 CLA isomers (CLA 50:50); (2). mixture of 80% c9,t11 CLA and 20% t10,c12 CLA isomers (CLA 80:20); and (3). sunflower oil fatty acids (reference). The treatments were given as supplements in softgel capsules providing a total of 1.7 g (c9,t11+t10,c12) CLA fatty acids (50:50) or 1.6 g (c9,t11+t10,c12) CLA glycerides (80:20) per day in treatment groups for 12 weeks. RESULTS: Almost twice as many subjects reached protective antibody levels to hepatitis B when consuming CLA 50:50 fatty acids (15/24, 62%) compared with subjects consuming the reference substance (7/21, 33%, P=0.075). In subjects consuming CLA 80:20 glycerides this was 8/22 (36%). Other aspects of immune function, ie DTH responses, NK cell activity, lymphocyte proliferation and production of TNF-alpha, IL1-beta, IL6, IFN-gamma, IL2, IL4, and PGE(2), were not affected. CONCLUSION: This is the first study that suggests that CLA may beneficially affect the initiation of a specific response to a hepatitis B vaccination. This was seen in the CLA 50:50, but not in the CLA 80:20 group.

Adult↗

Incubation period and immune function: a comparative field study among coexisting birds.

Developmental periods are integral components of life history strategies that can have important fitness consequences and vary enormously among organisms. However, the selection pressures and mechanisms causing variation in length of developmental periods are poorly understood. Particularly puzzling are prolonged developmental periods, because their selective advantage is unclear. Here we tested the hypotheses that immune function is stronger in species that are attacked at a higher rate by parasites and that prolonged embryonic development allows the development of this stronger immune system. Through a comparative field study among 12 coexisting passerine bird species, we show that species with higher blood parasite prevalence mounted stronger cellular immune responses than species with lower prevalence. These results provide support for the hypothesis that species facing greater selection pressure from parasites invest more in immune function. However, species with longer incubation periods mounted weaker cellular immune responses than species with shorter periods. Therefore, cellular immune responses do not support the hypothesis that longer development time enhances immunocompentence. Future studies should assess other components of the immune system and test alternative causes of variation in incubation periods among bird species.

Adaptation, Physiological↗

[Effects of probiotics additives EM on growth metabolism and immune function of blue fox in growth phase].

Different doses of probiotics EM were added to the diets of blue fox in its growth phase to study the effects of EM additives on its growth, digestion metabolism and immune function. The results showed that with EM additives applied, the ingestion and average daily gains were increased remarkably (P < 0.05). The apparent digest rate of crude fibre, crude protein, mineral elements Ca, P and NPU could be increased (P < 0.05) and correlated with its dose, and the digest rates of the later four targets in group III were increased by 8.21%, 16.27%, 9.82%, and 12.13%, respectively. EM additives could not increase the digest rate of ether extral and N-free extract. Disease of diarrhoea and blood in stool could be prevented and cured, and immune function and the survival rate of fox in growth phase could be increased remarkably. EM, which a kind of efficient, safe and environmental protection additives, can be extended and applied in farming of fur animals.

Animals↗

Physiological levels of 5 alpha-dihydrotestosterone depress wound immune function and impair wound healing following trauma-hemorrhage.

HYPOTHESIS: Studies indicate that a depressed wound immune function contributes to an increased rate of wound complications and impaired wound healing following trauma-hemorrhage (T-H). Androgen, ie, 5 alpha-dihydrotestosterone, is responsible for producing the depressed systemic cell-mediated immune responses following T-H in males. The aim of the present study was to determine whether depletion of 5 alpha-dihydrotestosterone in males before T-H has any salutary effects on wound immune cell function and wound healing in male mice following T-H. DESIGN: Mice were castrated or sham castrated 14 days before midline laparotomy (ie, tissue trauma) and subcutaneous polyvinyl sponge implantation, followed by hemorrhage (mean +/- SEM blood pressure, 35 +/- 5 mm Hg for 90 minutes and resuscitation) or sham operation. At 24 hours thereafter, wound immune cells from the sponges were harvested and cultured with lipopolysaccharide A. Release of interleukin 1 beta (IL-1 beta) and IL-6 (in picograms per milliliter) was determined in the supernatants by enzyme-linked immunosorbent assay. In addition, IL-6 was assessed at the wound site by immunohistochemistry. Ten days after T-H, wound-breaking strength was measured. RESULTS: Precastration prevented the significantly suppressed capacity of wound immune cells to release IL-1 beta and IL-6. In addition, precastration normalized the elevated IL-6 expression at the wound site in the T-H mice. Moreover, wound-breaking strength was improved in castrated mice 10 days after T-H. CONCLUSIONS: Male sex steroids appear to be responsible for wound immune cell dysfunction following trauma and severe blood loss. Because decreasing androgen levels resulted in improved wound healing, our results suggest that the use of androgen receptor-blocking agents, eg, flutamide, following T-H might represent a novel adjunct for decreasing the rate of wound complications under those conditions.

Analysis of Variance↗

Gelatinase B: a tuner and amplifier of immune functions.

Gelatinase B (matrix metalloproteinase-9) is a secreted multidomain enzyme that is important for the remodeling of the extracellular matrix and the migration of normal and tumor cells. It cleaves denatured collagens (gelatins) and type IV collagen, which is present in basement membranes. In the immune system, this cleavage helps lymphocytes and other leukocytes to enter and leave the blood and lymph circulations. Gelatinase B also cleaves myelin basic protein and type II gelatins, and this clipping leads to remnant epitopes that generate autoimmunity, the so-called REGA model of autoimmunity. Recently, gelatinase B has been found to process cytokines and chemokines, resulting in skewed immune functions. Therefore, gelatinase B, often considered as a pure effector molecule, acts as a switch and catalyst in both innate and specific immunity, and constitutes a prototypic example of the regulation of immune functions by proteolysis.

Animals↗

Immune function in severe, active rheumatoid arthritis. A relationship between peripheral blood mononuclear cell proliferation to soluble antigens and synovial tissue immunohistologic characteristics.

The immunohistology of synovium from a tender, swollen knee and peripheral blood cellular immune function were correlated in 24 clinically similar patients with active, seropositive rheumatoid arthritis who were not taking cytotoxic or long-acting antirheumatic drugs. The patients were classified as anergic (n = 6) or nonanergic (n = 18) on the basis of peripheral blood mononuclear cell proliferative responses to a battery of soluble recall antigens. The peripheral blood mononuclear cells of anergic patients failed to respond significantly to any soluble recall antigen, whereas cells from nonanergic patients responded to at least one such antigen. Multiple pieces of synovial tissue were obtained from each patient at arthroscopy. To minimize intrajoint variability, all pieces were analyzed and averaged to determine a composite profile of abnormalities. Synovial specimens from all six anergic patients had "high intensity" lymphocytic infiltration (group A). In sharp contrast, synovial specimens from 15 of 18 nonanergic patients had "low intensity" lymphocytic infiltration (group B) (P = 0.002). Group A tissues typically showed higher intensity T cell and plasma cell infiltration, more synovial lining layer hyperplasia, more HLA-DR bearing cells, and a higher ratio of Leu 3A/Leu 2A T cells than did group B. Group B tissues had fewer infiltrating cells (most of which were OKM1 and HLA-DR bearing), more extensive fibrin deposition, and far fewer T and plasma cells. Although these data do not imply that synovium from different joints in an individual patient are immunohistologically identical, they do provide evidence that peripheral blood mononuclear cell immune function reflects immunopathologic events in the biopsied joint. Moreover, the data further support the view that clinically active rheumatoid arthritis is, like certain other chronic inflammatory conditions, a heterogeneous disorder with polar subgroups.

Antigens↗

Cellular immune function in mice tolerant to or abstinent from l-trans-delta 9-tetrahydrocannabinol.

The effects of tolerance to l-trans-delta 9-tetrahydrocannabinol (THC) following repeated administration and of subsequent abstinence following drug withdrawal on the cellular immune function were determined in female B6C3F1 mice. Mice were injected with THC (10 mg/kg s.c.) twice daily for 4 days. On day 5, analgesic response to various doses of THC was determined using the tail flick test. Similarly, hypothermic response to THC was also determined. Multiple injections of THC resulted in the development of tolerance to both the analgesic and hypothermic effects of THC. Immune function studies were performed on mice rendered tolerant to or abstinent from THC by these procedures. Neither tolerance nor abstinence subsequent to a 4-day THC administration had any effect on either body weight or thymus weight and cellularity, although both spleen weight and cellularity were decreased in THC-abstinent animals. Likewise, no significant effects on B cell proliferation were observed in either tolerant or abstinent mice. The production of the cytokine interleukin-2 by T helper cells was markedly suppressed in both tolerant and abstinent mice, whereas the production of interleukin-4 was significantly suppressed only in THC-abstinent mice. Significant suppression of tumor cell cytolysis mediated by cytotoxic T cells and natural killer cells was only observed in THC-abstinent mice. These results suggest that THC-mediated modulation of the immune response may result from a differential effect on cellular populations.

Analgesics↗

Cimetidine preserves non-specific immune function after colonic resection for cancer.

Fifty consecutive patients undergoing resection of colorectal cancer were randomized to either receive cimetidine at a dose of 400 mg bd for a minimum of 5 pre-operative days, then intravenously for 2 postoperative days, or to act as controls. Baseline immune function was determined in all patients by in vitro testing of lymphocyte proliferation (LP) in response to mitogen, skin testing for cell mediated immunity (CMI) and measurement of lymphocyte subsets. Immune function was retested in both groups on the second postoperative day. In control patients the mean postoperative LP value was 41% of pre-operative levels (P < 0.0001) and the mean CMI reduced to 29% (P < 0.0001). Patients treated with cimetidine had no significant fall in these parameters. Numbers of T and natural killer (NK) cells fell after surgery in both groups, and B cell numbers were maintained in the cimetidine group. It is concluded that cimetidine reduces the immunosuppression that follows colonic resection.

Aged↗

Depressed immune functions in the early phase of varicella-zoster virus reactivation.

Varicella-zoster virus (VZV) infections are among the most common viral diseases characterized by recurrent episodes alternating with asymptomatic periods. VZV reactivation is believed to be induced by the impairment of the host's cell-mediated immune system; however, the precise mechanisms involved in the latency period and reactivation of herpes viruses in the infected host are not yet fully elucidated. We assessed the immune functions in noncompromised patients with typical herpes zoster to investigate the immunological status during the process of reactivation of VZV. The results indicated depressed immune functions in the early stage of VZV reactivation with gradual improvement during the recovery phase. These findings are in accord with the clinical course of herpes zoster and suggest a possible therapeutic trial.

Adult↗

Reduction of blood pressure and restoration of T-cell immune function in spontaneously hypertensive rats by food restriction and/or by treadmill exercise.

The studies were carried out to compare the effects of food restriction and/or treadmill exercise on the development of high blood pressure and to compare immune function in spontaneously hypertensive rats (SHR). The results demonstrate that moderate food restriction from weaning or a regular treadmill exercise not only maintains significantly lower blood pressure, but also increases T-cell proliferative response against mitogens which is found to be significantly depressed in SHR fed ad libitum. A significant loss of T-cell subpopulation such as W3/25+ T helper cells and OX8+ non-helper T-cells occurring in mice fed ad libitum were restored to normal levels, including IL-2 response, in food-restricted SHR. Our results suggest that both food restriction and/or physical exercise is effective in modulating the blood pressure and increasing T-cell immune functions in SHR.

Animals↗

Assessing relative risks of infection and rejection: a meta-analysis using an immune function assay.

BACKGROUND: Long-term use of immunosuppressants is associated with significant morbidity and mortality in transplant recipients. A simple whole blood assay that has U.S. Food and Drug Administration clearance directly assesses the net state of immune function of allograft recipients for better individualization of therapy. A meta-analysis of 504 solid organ transplant recipients (heart, kidney, kidney-pancreas, liver and small bowel) from 10 U.S. centers was performed using the Cylex ImmuKnow assay. METHODS: Blood samples were taken from recipients at various times posttransplant and compared with clinical course (stable, rejection, infection). In this analysis, 39 biopsy-proven cellular rejections and 66 diagnosed infections occurred. Odds ratios of infection or rejection were calculated based on measured immune response values. RESULTS: A recipient with an immune response value of 25 ng/ml adenosine triphosphate (ATP) was 12 times (95% confidence of 4 to 36) more likely to develop an infection than a recipient with a stronger immune response. Similarly, a recipient with an immune response of 700 ng/ml ATP was 30 times (95% confidence of 8 to 112) more likely to develop a cellular rejection than a recipient with a lower immune response value. Of note is the intersection of odds ratio curves for infection and rejection in the moderate immune response zone (280 ng/ml ATP). This intersection of risk curves provides an immunological target of immune function for solid organ recipients. CONCLUSION: These data show that the Cylex ImmuKnow assay has a high negative predictive value and provides a target immunological response zone for minimizing risk and managing patients to stability.

Graft Rejection↗

Effects of combined radiation and thermal burn injury on the survival of skin allograft and immune function in rats.

OBJECTIVES: To investigate the effects of combined radiation and thermal burn injury on the survival of skin allografts and to analyze the relationship between the prolongation of allograft survival and the changes of immune functions of the thymocytes and splenocytes in rats. METHODS: Wistar rats were irradiated with 3, 4, 5, 6 and 8 Gy of gamma rays. Thirty minutes after radiation, 15% TBSA III-degree burn was inflicted to the rats. Twenty-four hours after the burn injury, allografts were used to cover the burn wounds. In the 8 Gy group, 1 hour before skin grafting, the bone marrow cells (4 x 10(8)) from the same donor were also transplanted. All rats were carefully observed after injury. The rats with single radiation injury of 5 Gy gamma rays, with single burn injury and with combined radiation-burn injury were killed 3, 7, 10, 15 and 30 days after skin grafting for immunological assay and pathological study. RESULTS: All the allografts in the single burn group were rejected in 10 days. In the combined injury groups, the survival rates of the allografts in rats undergoing 3 and 4 Gy radiation were 20% and 30%, respectively. In the combined injury groups undergoing 5, 6 and 8 Gy radiation, the 10-day survival rates of the allografts were 69%, 88% and 100% respectively, and the 30-day survival rates in the three groups were 36%, 42% and 100% separately. The grafted allogenic skin, with normal epithelial cells and good vascularity, healed well with the recipient's skin. Hairs grew well from the allografts 30 days after grafting. Three, 7 and 15 days after allografting, in the single burn group, the proliferative activities of the thymocytes were 90%, 185% and 130% of the preinjury level, and the antibody forming capacities of the splenocytes were 200%, 171% and 300% of the preinjury level, respectively; in the combined injury groups, the proliferative activities were 6%, 99% and 91% of the preinjury level, and the forming capacities were 2%, 36% and 90% of the preinjury level. CONCLUSIONS: The survival rate of allograft in rats undergoing combined radiation and thermal burn injury rises with the increase in radiation dosage. The allograft covering single bun injury is severely rejected by immune reaction. The prolongation of the survival of allograft in combined injury group mainly results from radiation that suppresses immune functions.

Animals↗

Reduction of immune function in life stress and depression.

Reduced cell-mediated immune function has been found in depressed patients and in distressed persons undergoing threatening life events. The present study examines the interaction between severe life stress and major depression to produce immune alterations in 36 matched pairs of hospitalized depressed patients and nondepressed controls. Both major depressive disorder and the presence of threatening life events in control subjects are independently associated with a 50% reduction of natural killer (NK) cytotoxicity. A decrease in natural cytotoxicity is significantly associated with depressive symptoms but not with age, alcohol consumption, or tobacco smoking. These findings of altered immunity provide further evidence that the physiological responses in chronic stress parallel those found in the syndrome of depression.

Adult↗

Controlled trial of zinc supplementation during recovery from malnutrition: effects on growth and immune function.

To evaluate the effect of zinc on growth and immune function, 32 marasmic infants were selected on admission to the nutrition recovery center; 16 received 2 mg/kg daily of elemental zinc supplement as acetate and the remaining received a placebo. Immunity was assessed by skin-test response, T-cell blastic proliferation immunoglobulins, and infectious morbidity. Weight-for-length gain for initial 60 days in Zn-supplemented group was 9% of standard vs 3% for placebo (p less than 0.05). Energy intake was similar in both groups. Incidence of infections, especially pyoderma, was significantly higher in placebo group: 10 of 16 vs 3 of 16 in the supplemented group (p less than 0.025). Plasma Zn was correlated with number of febrile days in the prospective month (r = -0.66, p less than 0.05). The percent anergic infants decreased and serum IgA increased significantly only in Zn-supplemented group. Zinc supplementation has significant effects on weight gain and host defense mechanisms despite normal plasma levels. Zinc supplementation is recommended for optimal recovery from marasmus.

Anthropometry↗