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Chronic methamphetamine exposure alters immune function in normal and retrovirus-infected mice.

Methamphetamine (MA) abuse represents a growing problem in the USA with an increase of sudden death. To evaluate the immune function alterations due to chronic methamphetamine use, we examined C57BL/C mice with LP-BM5 retrovirus infection plus methamphetamine exposure. Mice were randomly assigned to the following groups: placebo, placebo retrovirus-infected, uninfected MA treated and retrovirus-infected MA treated. Placebo, MA-treated groups were intraperitoneally injected with saline, MA, respectively, with a gradually increasing dose from 15 to 40 mg/kg for 12 weeks (5 days/week). Con A- and LPS-induced mitogenesis of splenocytes, cytokine production by splenocytes culture and lipid peroxides in the liver were measured. Heart tissue histopathology was analyzed in all the groups with murine cytomegalovirus (CMV) superinfection. Our data showed that MA treatment significantly decreased production of IL-2 and interferon gamma (IFN-gamma) in uninfected mice but did not further suppress the reduced Th1 cytokines in retrovirus-infected mice. There were no significant effects on cytokines IL-4 and IL-6. However, tumor necrosis factor (TNF-alpha) was significantly increased in both uninfected and infected mice due to MA treatment. Lipid peroxides in liver were significantly increased both in uninfected and retrovirus-infected mice due to MA exposure. Vitamin E levels in liver were significantly decreased in uninfected mice due to MA treatment. CMV superinfection greatly increased the cardiac lesions in retrovirus-infected mice while no significant histopathology changes were detected due to MA treatment. Our data suggest that MA has immunomodulation activity, suppressing Th1 cytokine production and enhancing some Th2 cytokine secretion, as well as increasing lipid peroxides in uninfected mice. The interaction between LP-BM5 and MA remains unclear.

Animals↗

Chronically stimulated microglial cells do no longer alter their immune functions in response to the phagocytosis of apoptotic cells.

In an autoimmune inflammatory setting, ingestion of apoptotic T cells leads to a down-regulation of microglial immune functions. Recent studies have indicated that microglia can be matured by exposure to GM-CSF. GM-CSF stimulation led to a differentiated microglial phenotype and enhanced antigen-presenting capabilities. The secretion of TNF-alpha was significantly decreased by the uptake of apoptotic cells in unstimulated microglia, but not in GM-CSF-differentiated microglia. IL-10 secretion was unaffected. After ingestion of apoptotic cells, only previously unstimulated, but not GM-CSF-differentiated microglial cells decreased their T cell-activating potential as measured by IFN-gamma secretion in antigen-activated MBP-specific T cells. Thus, GM-CSF stimulation reduces the immunomodulatory functions of microglial cells.

Adjuvants, Immunologic↗

[Effect of human recombinant-gamma interferon on the immune function of peripheral blood lymphocytes in cancer patients].

We administered recombinant gamma-interferon (ReIFN-gamma) daily to 7 cancer patients, and the effect on the immune function of peripheral blood lymphocytes was studied. Following the administration of ReIFN-gamma, no characteristic changes were observed in leukocyte count, lymphocyte count, OKT4/OKT8 or Leu 7. Natural killer cell cytotoxicity was augmented in all cases from the first week of administration and retained a high level of activity during the period of treatment. In contrast, the blastogenesis of PBL with PHA decreased from the first week. Suppressor cell activity was augmented from the first week and maintained throughout this period. As to clinical effect, two patients who had metastatic liver tumors showed a response to the administration of ReIFN-gamma.

Aged↗

Effect of thyrotropin-releasing hormone on immune functions of peripheral blood mononuclear cells.

The tripeptide thyrotropin-releasing hormone (TRH) works as a hypothalamic hormone, but is found also outside the brain in intrinsic nerve fibers of the gastrointestinal tract. There is evidence that TRH modulates the activity of immunocompetent cells, although there are only very few data on TRH-mediated immune effector functions. Since we could recently show that TRH inhibits monocyte activities we were also interested in other possible TRH modulated immune functions. Peripheral blood mononuclear cells (PBMC) from ten healthy subjects were cultured for 7 days and pulsed with 0.125 and 0.250 microgram/ml Pokeweed mitogen (PWM). 10(-12) to 10(-6) M TRH was added simultaneously with PWM. Lymphocyte proliferation [(3H]thymidine incorporation), interferon-gamma (IFN-gamma) activity (RIA) and immunoglobulin activities (IgG, IgM, IgA; ELISA) were determined in the supernatants. We could demonstrate a TRH-dependent decrease in PWM-pulsed IgG activity with significant (alpha = 0.05) values at 10(-8) and 10(-10) M (-29 +/- 6%/-16 +/- 3% for PWM 0.125 microgram/ml and -17 +/- 9%/-11 +/- 9% for PWM 0.250 microgram/ml). This inhibitory effect could be abolished by an anti-TRH antiserum. There was no TRH effect on IgM and IgA activities, IFN-gamma activity and lymphocyte proliferation compared with the PWM stimulated values alone. The described TRH effect on the polyclonal IgG response by PBMC gives further evidence for a functional link between the immune system and the endocrine system, although its underlying mechanism is not yet clear.

Enzyme-Linked Immunosorbent Assay↗

Circumscribed lesion of the medial forebrain bundle area causes structural impairment of lymphoid organs and severe depression of immune function in rats.

Interactions between the immune system and the brain are a key element in the pathophysiology of diseases such as multiple sclerosis, neuroAIDS, and Alzheimer's, which affect large numbers of individuals and are associated with a high social cost. However, the neuroanatomical basis of brain-immune interactions has not been elucidated. We report that in Wistar rats of either sex bilateral electrolytic lesion of the medial forebrain bundle reduces body weight by 28% 7 days after lesioning, and causes widespread infections, aphagia, adypsia, structural damage to the lymphoid organs and heavy depression of T lymphocytes cytotoxicity. The following alterations occur in the immune system after those lesions: the weight of the thymus, spleen and lymphonodes is reduced by 77.9%, 49.1% and 48.4%, respectively. The thymus is atrophied and contains fewer lymphoid cells in the cortex than in the medulla. In the spleen the white pulp is reduced and lymphoid cells from periarteriolar zones and at the chords are almost absent. In lymph nodes cortical small lymphocytes are depleted and primary and secondary nodules and germinal centers all but disappear. Cytotoxicity of lymphocytes is reduced by 86.2% in the thymus, 77.6% in the spleen and 70.2% in lymph nodes. The critical area of lesion is at the medialmost portion of the medial forebrain bundle, at the preoptic area and rostral part of the anterior hypothalamus. We suggest that this area contains neural circuits that are crucial for keeping the structure of lymphoid organs and the functional integrity of the immune system.

Animals↗

[Study on induction of dendritic cells from myeloid leukemia cell lines and their antitumor immune function].

Dendritic cell (DC) plays a key role in antitumor immune response. However, there is a deficiency of DC function in the majority of leukemia patients. It is a novel idea that expanding DC in vitro and enhancing their antitumor immune function and DC-based tumor vaccines may be used as an efficient immune therapy for leukemia. In the project, the condition to induce DC from myeloid leukemia cell lines and its anti-leukemia response were investigated. HL-60, K562 and THP-1 cells were cultured with various combinations of cytokines for inducing DC. The morphologic features were analyzed with optical and electron microscopy. The phenotype of DC was detected by FCM with CD1a, CD40, CD80, CD86, HLA-A, B, C and HLA-DR monoclonal antibodies. The ability of DC stimulating lymphocyte proliferation was observed by allo-mixed lymphocyte reaction using (3)H-TdR incorporation. Cytotoxicity assay was measured by (51)Cr-release method. The level of IL-12 and IFN-gamma in supernatant of DC culture was measured by ELISA. It was proved that the DCs derived from K562, HL-60 and THP-1 cells showed a typical morphology of dendritic cell. The induced cells expressed the surface differentiation antigens of DC. A high expression of phenotypes was found in HL-60-DC and THP-1-DC stimulated by GM-CSF + IL-4 + TNF-gamma and K562-DC with GM-CSF + IL-4 + IL-12. The DCs from the 3 leukemia cell lines stimulated allo-MLR and CTL reaction strongly. Different contents of IL-12 were detected in the supernatants of DC culture and IFN-gamma in the coculture of DC and blood mononuclear cells. It is concluded that the myeloid leukemia cells are able to be induced DCs by cytokines in vitro. The different leukemia cells need different cytokines and cultural conditions. DCs derived from leukemia cells express phenotype of antigen-presenting cells. They have the ability of stimulating T lymphocyte proliferation and inducing CTL reaction to clear leukemia cells, and the DCs secrete IL-12 and increase secretion of IFN-gamma by T cells.

Antigens, CD↗

Effects of transfusion on immune function. Cancer recurrence and infection.

The paradigm related to the immunologic consequences of allogeneic blood transfusions has been extended from humoral allosensitization to the effects of transfusion on cellular immune function. This includes downregulation of effector cells, activation of latent viral infection, and the prolonged circulation of donor immunocompetent cells, as seen in graft-vs-host disease. There are now extensive data showing conclusively that allogeneic transfusions are associated with increases in cancer recurrence rates (80% in colorectal cancer) and postoperative bacterial infections (as much as 200% to 1000% in some studies). Whether these associations are causal or not remains in doubt. Based on animal and clinical studies, we believe these associations are likely, in part, due to immune dysregulation caused by transfusion, perhaps augmented by the effects of hemorrhage, anesthesia, and surgical stress. The most likely mechanism underlying transfusion-induced immunosuppression is anergy due to presentation of large amounts of antigen through the intravenous route. This favors presentation of antigen by "nonprofessional" antigen-presenting cells, a situation that usually leads to anergy or tolerance rather than immune activation. Two additional hypothetical mechanisms proposed for immune dysregulation after allogeneic transfusion are (1) prolonged circulation of donor cells causing subclinical graft-vs-host disease, and (2) reactivation of immunosuppressive viruses latently present in recipient white blood cells. Results of some initial interventional studies, employing autologous transfusions or removing white blood cells from allogenic donor blood suggest that relatively simple, cost-effective strategies to ameliorate these complications may be at hand.

Bacterial Infections↗

Effect of intrathecal morphine and electro-acupuncture on cellular immune function of rats and increment of mu-opioid receptor mRNA expression in PAG following intrathecal morphine.

The present study was to investigate the dynamic changes of cellular immune function of rats with intrathecal injection of (ith) morphine and the regulatory effect of electroacupuncture(EA) stimulation on "Zusanli" (St.36) and "Lanwei" (Extra 37) points. The results showed that ConA-induced rat spleen lymphocyte proliferation was significantly decreased on 2h, 4h, 8h, 12h, 24h, 48h after ith morphine(40microg/50microL). The proliferative response was recovered to nearly normal on 72h. EA on corresponding periods could prevent the decrease of lymphocyte proliferative response of rats induced by ith morphine. The same tendency was observed on the induction of IL-2 production. Further study continued to explore the mechanism of the potentiating effect of mu-opioid receptor in periaqueductal gray (PAG) and hippocampus on the immunosuppression induced by ith morphine at molecular level with in situ hybridization histochemistry technique. The results showed that ith morphine could increase the expression of mu-opioid receptor mRNA.

Analgesics, Opioid↗

Effect of age, breed and dietary omega-6 (n-6): omega-3 (n-3) fatty acid ratio on immune function, eicosanoid production, and lipid peroxidation in young and aged dogs.

The focus of this study was to examine the influence of age and diet on various parameters of immune function in young and old Fox Terriers and Labrador Retrievers. Eighteen young and old dogs were utilized for this study. Young and old dogs were fed a basal diet containing an (n-6):(n-3) ratio of 25:1 for sixty days (Phase I). Half of the dogs were then switched to a diet with an (n-6):(n-3) ratio of 5:1, and all were maintained on their respective diets for an additional sixty days (Phase II). Results from these studies revealed an age-associated decline in several immune parameters measured. Both these breeds demonstrated a reduction in sheep red blood cell titers, as well as in their ability to respond to different mitogens. Interestingly, this decline was greater in Fox Terriers, suggesting a decrease in cellular proliferative capacity in lymphocytes isolated from the larger breed. Neither cytokine production or DTH response was affected by age. Diet and breed interactions resulted in a significant increase in T- and B-cell mitogen responsiveness. In contrast, supplementation with n-3 fatty acids did not affect IL-1, IL-6 or TNF-alpha production. Supplementation with n-3 fatty acids resulted in increased PGE3 production from peritoneal macrophages but had no effect on PGE2 production from peripheral blood mononuclear cells or peritoneal macrophages. The n-3 fatty acid supplementation did not influence alpha-tocopherol status although older dogs had significantly lower serum alpha-tocopherol concentrations. Oxidative status of these dogs was assessed by serum levels of malondialdehyde (MDA) and 4-hydroxynonenal (4-HNE). Feeding an n-3-enriched diet did not affect 4-HNE levels but significantly decreased MDA levels in old dogs. In summary, this study indicates that feeding a diet containing an (n-6):(n-3) fatty acid ratio of 5:1 had a positive, rather than a negative, effect on the immune response of young or geriatric dogs.

Aging↗

Effect of dietary nucleotide supplementation on growth and immune function in term infants: a randomized controlled trial.

OBJECTIVE: To examine the effect of nucleotide (NT)-supplemented cow's milk-based formula on growth and biochemical indices of immune function in healthy infants. DESIGN: Randomized controlled trial (RCT) of formula-fed term infants allocated to control formula with an innate level of NT at 10 mg/l (n = 102), or formula fortified with NT at 33.5 mg/l (n = 98). A parallel group of 125 breastfed infants followed the same protocol as a reference. OUTCOME MEASURES: Growth was assessed at enrolment, 7 weeks, 4 months and 7 months of age. Natural killer cell activity, cytokine production and lymphocyte subpopulations were assessed at 7 weeks of age. Antibody responses to diphtheria toxoid, tetanus toxoid and Haemophilus influenzae type b (Hib) immunizations were measured at 7 months of age. RESULTS: NT supplementation did not influence the growth of formula fed infants or any markers of immunity measured at 7 weeks of age. Antibody responses to tetanus toxoid were higher in the NT-supplemented group (n = 68) compared with the control group (n = 70) at 7 months of age (median (5th, 95% percentile): 1.57(0.42, 3.43) vs 1.01(0.41, 4.66) IU/ml, P < 0.03). A difference between treatments was seen in response to diphtheria toxoid but this effect disappeared when adjusted for hepatitis B immunization at birth. There was no effect of treatment on antibody responses to Hib immunization. CONCLUSIONS: Supplementation of formulas with NT at 33.5 mg/l resulted in a modest improvement in antibody response consistent with RCTs that used higher levels of NT supplementation. Whether this translates to clinical benefits in well-nourished infants requires further study. SPONSORSHIP: Supported by a grant from Wyeth Nutrition. Dr Makrides was supported by an RD Wright Fellowship from the National Health and Medical Research Council of Australia and Dr Gibson was partially supported by the MS McLeod Research Trust and a Senior Research Fellowship from the National Health and Medical Research Council of Australia.

Antibodies, Bacterial↗

Impact of infectious disease upon fat metabolism and immune functions.

Abnormalities in lipid metabolism influence immunological competence. Infectious diseases are accompanied by altered lipid metabolism as well as by suppression or stimulation of generalized defensive mechanisms and immune functions. An infectious disease may therefore introduce variables that must be recognized and evaluated during studies aimed at elucidating possible relationships between dietary lipids and the development of cancer.

Cholesterol↗

Unimpaired immune functions after laparoscopic cholecystectomy.

BACKGROUND: The advantages of laparoscopic cholecystectomy over the open procedure seem to be related to the lesser surgical trauma. Whether this is also reflected by reduced postoperative immune suppression is not known. METHODS: The perioperative cellular immunocompetence of patients undergoing either laparoscopic (n = 8) or open (n = 8) cholecystectomy was evaluated before operation and at 24 hours and 6 days after operation for inflammatory reactivity by white blood cell counting and serum interleukin-6 assessment. Immunocompetence was evaluated by skin testing with phytohemagglutinin and by phenotyping blood mononuclear cells. RESULTS: Although 24 hours after conventional cholecystectomy granulocyte and interleukin-6 levels were strongly increased, laparoscopic cholecystectomy did not affect these acute inflammation parameters. Patients who had undergone conventional cholecystectomy showed a strong reduction of phytohemagglutinin responsiveness, in contrast to laparoscopic patients (67% versus 0% reduction). Flow cytometric analysis of blood mononuclear cells revealed a distinct reduction of HLA-DR expression on monocytes in the open cholecystectomy group only. Both parameters returned to baseline levels within 6 days after operation. CONCLUSIONS: In contrast to open cholecystectomy, laparoscopic cholecystectomy does not significantly affect parameters reflecting immunocompetence. This lack of interference with cellular immune functions provides another argument favoring laparoscopic rather than open cholecystectomy.

Adult↗

Monitoring immune function during immunosuppressive therapy.

Twenty-nine patients with a variety of connective tissue disorders were studied for the effects of immunosuppressive therapy on non-specific parameters of immune function. Baseline studies prior to therapy showed a frequent incidence of anergy (13%) lymphopenia (31%) and abnormal PHA response (43%). Despite these abnormalities in untreated patients it was possible to show an even higher incidence of anergy (31%), lymphopenia (66%) and abnormal PHA response (77%) following immunosuppressive treatment. The changes in lymphocyte count and PHA response were found to be statistically significant. It was found, paradoxically, that delayed hypersensitivity responses improved following institution of therapy in three patients. Clinical efficacy of immunosuppression correlated with lymphopenia and depressed PHA responses; in particular in the five patients with uncontrolled disease, these parameters were normal. Lymphocyte counts and PHA responses are the most simple and informative procedures to monitor immunosuppression in patients.

Collagen Diseases↗

[The influence of the application of cytotoxic lymphocyte antigen 4-Ig adenovirus on the burn wounds with alloskin grafting on the murine immune function].

OBJECTIVE: To investigate the influence of local application of cytotoxic lymphocyte antigen 4-Ig (CTLA4-Ig) adenovirus on the burn wound with alloskin grafting upon the murine immune function. METHODS: Sixty BALB/c mice were randomly divided into A (operation control), B (CTLA4-Ig transfection) and C (normal control) groups, with 20 mice in each group. Skin wounds (full-thickness loss) sized 1.5 cm x 1.5 cm were created on the backs of mice in A and B groups. Then the skin grafts of the same size obtained from C57BL mice were grafted into the skin wounds. 0.1 g of cross-linking polyacrylic resin (carbomer cream) without adenovirus was daubed onto the wounds in A group, and the same amount of carbomer cream with adenovirus in titers of 5 x 10(9)/L was daubed onto the wounds in B group, while no treatment was given in C group. 1 ml of 10% SRBC (sheep red blood cell) was injected intraperitoneally to all the mice of the three groups on the 1st post injury day (PID). Splenocytes from BALB/c, C57BL and Kunming mice were harvested for mixed lymphocyte culture on 7, 14, 21 and 28 PIDs. Agglutination assay was used in the same time to detect the SRBC antibody titers. RESULTS: The reaction of murine splenocytes in B group to the donor (C57BL) splenocytes was suppressed in a specific way (P < 0.05) within 14 PIDs. There was no difference in the titers of anti-SRBC antibody among the 3 groups (P > 0.05). CONCLUSION: Local application of CTLA4-Ig recombinant adenovirus exhibited no influence on the murine humoral immunity, but might induce systemic and specific T cell tolerance in immunity system.

Adenoviridae↗

Development of a chicken 5 K microarray targeted towards immune function.

BACKGROUND: The development of microarray resources for the chicken is an important step in being able to profile gene expression changes occurring in birds in response to different challenges and stimuli. The creation of an immune-related array is highly valuable in determining the host immune response in relation to infection with a wide variety of bacterial and viral diseases. RESULTS: Here we report the development of chicken immune-related cDNA libraries and the subsequent construction of a microarray containing 5190 elements (in duplicate). Clones on the array originate from tissues known to contain high levels of cells related to the immune system, namely Bursa, Peyers patch, thymus and spleen. Represented on the array are genes that are known to cluster with existing chicken ESTs as well as genes that are unique to our libraries. Some of these genes have no known homologies and represent novel genes in the chicken collection. A series of reference genes (ie. genes of known immune function) are also present on the array. Functional annotation data is also provided for as many of the genes on the array as is possible. CONCLUSION: Six new chicken immune cDNA libraries have been created and nearly 10,000 sequences submitted to GenBank [GenBank: AM063043-AM071350; AM071520-AM072286; AM075249-AM075607]. A 5 K immune-related array has been developed from these libraries. Individual clones and arrays are available from the ARK-Genomics resource centre.

Animals↗

Sexual dimorphism in immune function: the role of prenatal exposure to androgens and estrogens.

Perinatal exposure to androgens permanently transforms certain tissues, e.g., the brain, the genitalia, etc. This process involves both masculinization and defeminization. Immune function also is transformed by early steroid exposure; however, it is not yet known whether the response capabilities of the immunocytes themselves are directly modified or whether they are responding to signals from other masculinized tissues, e.g., the brain. Most evidence points to a direct effect since androgen and estrogen receptors are present in developing immunocytes. Both androgens and estrogens have a role in regulating adult immunity including Th1/Th2 balance. Adult susceptibility to autoimmune and other diseases is also related to steroid exposure. How immune cells respond to gonadal steroids in adulthood may depend on the pattern of androgenic and estrogenic stimulation during early development.

Androgens↗

Immune function in hyperbaric environments, diving, and decompression.

The purpose of this review is to examine the influence of exposure to hyperbaric oxygen (HBO2) deep diving, and decompression on various facets of the immune response. Potential changes during exposure include a decrease in the CD4+:CD8+ ratio, a decreased proliferation of lymphocytes, and an activation of neutrophils with migration to regions of high oxygen pressure. There may also be an activation of the complement cascade during decompression. Clinical indicators of overall immune suppression include a decreased response to antigens, a weakening of autoimmune responses, and a slower rejection of allografts. In professional divers, immune changes are at least partially offset by acclimatization, and seem to have little clinical significance. However, patients receiving HBO2 are a more vulnerable group; in their case, exposure may impair immune surveillance, and a careful monitoring of immune function may be important to the success of treatment.

Animals↗

Evaluation of some immune functions in a patient affected by common variable immunodeficiency using luminescent techniques.

Common variable immunodeficiency is a primary immunodeficiency characterized by a failure of antibody synthesis, whose fundamental immunologic abnormality is still unknown. In our study, we evaluated some immune functions using chemiluminescence in a 32-year-old woman affected by common variable immunodeficiency. In particular, we showed an impairment of her lymphomonocyte proliferative response which was evaluated using a method based on the bioluminescent measurement of ATP. Besides, we found a reduction of her lymphomonocyte IL2 and IL4 production: the IL4 production was evaluated through an ELISA method, whereas the IL2 activity was determined by its ability to support the IL2-dependent murine T-cell line (CTLL) proliferation which was established through a method based on the bioluminescent measurement of ATP. Finally, we evaluated both yeast-induced and fMLP-induced polymorphonuclear and monocyte oxidative metabolism through a luminol-amplified chemiluminescence; these functions were within normal values. Therefore, in our patient affected by common variable immunodeficiency, we demonstrated an impairment of cellular immunity, which might contribute to the pathogenesis of the disease.

Adenosine Triphosphate↗