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Pediatric Critical Care Medicine : a... Dec 2022Immunoparalysis in children with septic shock is associated with increased risk of nosocomial infections and death. Myeloid-derived suppressor cells (MDSCs) potently... (Observational Study)
Observational Study
OBJECTIVES
Immunoparalysis in children with septic shock is associated with increased risk of nosocomial infections and death. Myeloid-derived suppressor cells (MDSCs) potently suppress T cell function and may perpetuate immunoparalysis. Our goal was to test the hypothesis that children with septic shock would demonstrate increased proportions of MDSCs and impaired immune function compared with healthy controls.
DESIGN
Prospective observational study.
SETTING
Fifty-four bed PICU in a quaternary-care children's hospital.
PATIENTS
Eighteen children with septic shock and thirty age-matched healthy children.
INTERVENTIONS
None.
MEASUREMENTS AND MAIN RESULTS
Peripheral blood mononuclear cells (PBMCs) were isolated from whole blood and stained for cell surface markers to identify MDSCs by flow cytometric analysis, including granulocytic and monocytic subsets. Adaptive and innate immune function was measured by ex vivo stimulation of whole blood with phytohemagglutinin-induced interferon (IFN) γ production and lipopolysaccharide (LPS)-induced tumor necrosis factor (TNF)-α production, respectively. Prolonged organ dysfunction (OD) was defined as greater than 7 days. Children with septic shock had a higher percentage of circulating MDSCs, along with lower LPS-induced TNFα and phytohemagglutinin-induced IFNγ production capacities, compared with healthy controls. A cut-off of 25.2% MDSCs of total PBMCs in initial samples was optimal to discriminate children with septic shock who went on to have prolonged OD, area under the curve equal to 0.86. Children with prolonged OD also had decreased TNFα production capacity over time compared with those who recovered more quickly ( p = 0.02).
CONCLUSIONS
This article is the first to describe increased MDSCs in children with septic shock, along with an association between early increase in MDSCs and adverse OD outcomes in this population. It remains unclear if MDSCs play a causative role in sepsis-induced immune suppression in children. Additional studies are warranted to establish MDSC as a potential therapeutic target.
Topics: Child; Humans; Myeloid-Derived Suppressor Cells; Shock, Septic; Tumor Necrosis Factor-alpha; Leukocytes, Mononuclear; Phytohemagglutinins; Lipopolysaccharides
PubMed: 36094492
DOI: 10.1097/PCC.0000000000003071 -
Veterinary Immunology and... Jan 2022Ferrets are nowadays frequently used as animal models for biomedical purposes; in many cases, immunosuppression of experimental animals is necessary. The aim of this...
Ferrets are nowadays frequently used as animal models for biomedical purposes; in many cases, immunosuppression of experimental animals is necessary. The aim of this study was to evaluate the effect of intramuscular dexamethasone administration (2 mg/kg as the initiation dose continued with 1 mg/kg q 12 h applied 5 times) on ferret's immune system. In comparison with ferrets which received the saline (n = 5), significantly lower total counts of leukocytes (P < 0.01), lymphocytes (P < 0.01) and monocyte (P < 0.05), as well as absolute numbers of CD4+CD8- (P < 0.01) and CD4-CD8+ (P < 0.01) subsets were noted in dexamethasone treated ferrets (n = 5) the first day after the treatment (D1). Absolute number of CD79+ lymphocytes remained unchanged throughout the experiment. The proliferation activity of lymphocytes in dexamethasone treated ferrets was lower only in D1 using concanavalin A (conA), phytohemagglutinin (PHA) and pokeweed mitogen (PWM); statistical significance was noted using PHA 40 (P < 0.05) and PWM 10 (P < 0.01). Lower neutrophil activity (P < 0.01) was detected in D1 after the dexamethasone treatment in both production of reactive oxygen species (chemiluminescence test) and ingestion of particles (phagocytosis assay). The dexamethasone treatment proved to be useful for short-term immunosuppression in ferrets. The results closely resembled data previously reported in human studies and indicate classification of ferrets as steroid-resistant species.
Topics: Animals; Dexamethasone; Ferrets; Immunosuppression Therapy; Lymphocyte Activation; Models, Animal; Phytohemagglutinins; Pokeweed Mitogens
PubMed: 34826685
DOI: 10.1016/j.vetimm.2021.110362 -
Biological Trace Element Research Feb 2022Mining is one of the main activities that drive the economy of Brazil. Mining activity is associated with risk of contamination of environment and local fauna by metals....
Mining is one of the main activities that drive the economy of Brazil. Mining activity is associated with risk of contamination of environment and local fauna by metals. Amphibians have a life cycle that requires a transition between aquatic and terrestrial environments, increasing their vulnerability to metal contamination in the water and substrate. Metals are ubiquitous, with high bioaccumulative and biomagnifying potential, and may lead to immune and endocrine disruption. In this study, we analyzed two different components of the innate immune response, bacterial killing ability (BKA) and phytohemagglutinin edema (PHA), and two stress biomarkers, corticosterone plasma levels (CORT) and the neutrophil to lymphocyte ratio (N:L), of toads (Rhinella diptycha) living in places contaminated by metals. Blood samples were collected pre- and post-restraint (1h), followed by an immune challenge with PHA and tissue collection (liver, spleen, and kidneys). Toads liver metal bioaccumulation did not correlate with the immune response or stress biomarkers. Post-restraint, animals had increased CORT and reduced BKA, independently of the collection site, and these variables were not correlated with liver metal bioaccumulation. Interestingly, toads with the larger spleen (immune organ) showed increased N:L post-restraint and greater edema after the PHA challenge. Our results indicate that toads living in metal-contaminated environments responded to acute stressor, activating the hypothalamic-pituitary-interrenal axis and the immune response. Keep tracking the physiological variables of these animals and the presence of metals in the environment and tissues should provide valuable health status indicators for the population, which is vital for proposing amphibian conservation strategies in these areas.
Topics: Animals; Bufonidae; Corticosterone; Lymphocytes; Neutrophils; Restraint, Physical; Stress, Physiological
PubMed: 33840055
DOI: 10.1007/s12011-021-02699-x -
The Journal of Poultry Science Jul 2022The objective of this study was to determine the effects of dietary soy saponin (SS) on the antioxidant and immune functions of laying hens. Two hundred seventy...
The objective of this study was to determine the effects of dietary soy saponin (SS) on the antioxidant and immune functions of laying hens. Two hundred seventy 22-week-old Hy-line gray layers were randomly allocated into three treatment groups: a control group (Control) fed a basal diet with low soybean meal and groups supplemented with 50 and 500 mg/kg SS (50 SS and 500 SS). After ten weeks, eight chickens from each treatment group were anesthetized and sacrificed to collect tissue samples. In the 50 and 500 SS groups, results showed that the levels of superoxide dismutase (SOD) in serum and spleen were elevated, and the content of malondialdehyde (MDA) in serum decreased. The mRNA levels of genes such as NF-E2-related factor 2 () in the ileum and and in the spleen were also upregulated. In addition, the skin irritation index of phytohemagglutinin (PHA), the number of serum white blood cells, and lymphocytes were elevated in the two groups. At the same time, the number of monocytes in the blood increased in the 50 SS group, and it was significantly higher in the 500 SS group. In addition, the mRNA levels of lysozyme () and in the spleen were upregulated, similar to the mRNA levels of zinc finger protein A20 () in the ileum. Furthermore, the mRNA levels of and in the ileum were downregulated. In conclusion, with supplementation of 50 and 500 mg/kg SS in low soybean meal diets, the antioxidant, and immune functions of laying hens were improved. More importantly, the target for SS to exert biological effects on laying hens may be in the intestine and spleen tissues.
PubMed: 35989694
DOI: 10.2141/jpsa.0210073 -
European Journal of Medicinal Chemistry Nov 2023Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca...
Voltage-gated potassium channel K1.3 inhibitors have been shown to be effective in preventing T-cell proliferation and activation by affecting intracellular Ca homeostasis. Here, we present the structure-activity relationship, K1.3 inhibition, and immunosuppressive effects of new thiophene-based K1.3 inhibitors with nanomolar potency on K current in T-lymphocytes and K1.3 inhibition on Ltk cells. The new K1.3 inhibitor trans-18 inhibited K1.3 -mediated current in phytohemagglutinin (PHA)-activated T-lymphocytes with an IC value of 26.1 nM and in mammalian Ltk cells with an IC value of 230 nM. The K1.3 inhibitor trans-18 also had nanomolar potency against K1.3 in Xenopus laevis oocytes (IC = 136 nM). The novel thiophene-based K1.3 inhibitors impaired intracellular Ca signaling as well as T-cell activation, proliferation, and colony formation.
Topics: Animals; Mammals; Potassium Channel Blockers; Potassium Channels; Potassium Channels, Voltage-Gated; Structure-Activity Relationship; T-Lymphocytes; Thiophenes; Immunosuppressive Agents
PubMed: 37454520
DOI: 10.1016/j.ejmech.2023.115561 -
Scientific Reports Jan 2021Whilst the immune system often varies seasonally and exhibits differences between males and females, the general patterns in seasonality and sex differences across taxa...
Whilst the immune system often varies seasonally and exhibits differences between males and females, the general patterns in seasonality and sex differences across taxa have remained controversial. Birds are excellent model organisms to assess these patterns, because the immune system of many species is well characterised. We conducted a meta-analysis using 41 wild bird species from 24 avian families to investigate sex differences and seasonal (breeding/non-breeding) variations in immune status, including white blood cell counts, phytohaemagglutinin (PHA) test, bacteria-killing ability (BKA), haemolysis and haemagglutination assays. We found male-biased macrophage concentration, BKA and haemolysis titers, but only during the breeding season. Sex-specific heterophil concentrations, heterophil/lymphocyte ratios and PHA responses differed between breeding and non-breeding, suggesting larger changes in males than in females. Importantly, sex differences in immune status are stronger during the breeding period than during the non-breeding period. Taken together, our study suggests that both seasonal variation and sex differences in immune system are common in birds, although their associations are more complex than previously thought.
Topics: Animals; Birds; Female; Leukocyte Count; Leukocytes; Male; Seasons; Sex Characteristics
PubMed: 33446785
DOI: 10.1038/s41598-020-80030-9 -
Frontiers in Immunology 2022Allergic asthma is a chronic airway inflammatory disease associated with airway mucus hyper-production. ILC2 cells, which express the Th2 transcription factor GATA3,...
BACKGROUND
Allergic asthma is a chronic airway inflammatory disease associated with airway mucus hyper-production. ILC2 cells, which express the Th2 transcription factor GATA3, have been associated with allergic asthma. The cytokine IL-3 is known to support eosinophil, basophil and mucosal mast cell differentiation and survival; however, its role on T regulatory cells as well as on lung ILC2 and in pediatric asthma needs further investigation.
OBJECTIVES
To investigate the role of IL-3 in preschool children and to explore its therapeutic role in experimental asthma.
METHODS
In a cohort of preschool children with and without asthma, we analyzed the secretion of IL-3 in nasopharyngeal fluid (NPF) and IL-3 receptor (R) alpha chain mRNA expression in peripheral blood mononuclear cells (PBMCs). In a murine model of allergic asthma, we analyzed the phenotype of wild-type untreated and rIL-3 intranasally treated asthmatic mice.
RESULTS
IL-3 was found downregulated in the nasopharyngeal fluid of children with partially controlled asthma, as compared to control children. Moreover, IL-3 was found induced in phytohemagglutinin (PHA)-stimulated PBMCs from children with asthma and treated with steroids. Finally, IL-3 in NPF directly correlated with the anti-inflammatory molecule sST2 in steroid-treated asthmatic children. Intranasal rIL-3 delivery during the challenge phase decreased airway mucus production and inflammatory eosinophils. Moreover, rIL-3 given during the challenge phase, reduced lung ST2GATA3+ILC2, accompanied by an induction of T regulatory cells in the airways.
CONCLUSIONS
IL-3 was found associated with steroid-resolved asthma. Moreover, treatment with rIL-3 resulted in amelioration of airway eosinophilia and mucus production, two main pathophysiological conditions associated with asthma in a murine model of allergic asthma. Thus, rIL-3 opens new strategies for immunotherapy of this disease.
Topics: Animals; Asthma; Disease Models, Animal; Humans; Immunity, Innate; Interleukin-3; Leukocytes, Mononuclear; Lymphocytes; Mice; Mice, Knockout
PubMed: 35281014
DOI: 10.3389/fimmu.2022.821658 -
Tropical Animal Health and Production Mar 2022The objective of this study was to compare the behavioural and immunological responses of twin lambs housed together with their siblings or not after weaning. The study...
The objective of this study was to compare the behavioural and immunological responses of twin lambs housed together with their siblings or not after weaning. The study was performed with seven multiparous Milchschaf ewes and their twin lambs (n = 14), which were weaned abruptly at 63 days of age and assigned to two experimental groups: (1) lambs that were housed together with their sibling after weaning (group GT, n = 6) and (2) lambs that were separated from their siblings and remained with other lambs from the same flock (group GS, n = 8). Before and after weaning, the distance between twins, the number of times in which the sibling was the closest lamb, the lambs' behaviours, and the average daily gain were recorded. The lambs' immune response was assessed with the phytohemagglutinin skin test after weaning. The closest lamb before weaning was the sibling in all cases (P < 0.0001 for all). The frequency in which GT lambs were observed closest from its twin increased on the day of weaning (P = 0.002). During the day of weaning, GT lambs vocalised and paced more than GS lambs (P = 0.001 and P = 0.01, respectively). Twenty-four h after the phytohemagglutinin injection, the skinfold thickness was greater in GS than GT lambs (P = 0.03). In conclusion, twin lambs housed together with their siblings were more stressed at weaning, displaying more intensive behavioural changes and a poorer immunological status than twin lambs housed separated from their siblings.
Topics: Animals; Female; Sheep; Sheep, Domestic; Weaning
PubMed: 35235062
DOI: 10.1007/s11250-022-03121-x -
Frontiers in Immunology 2021The differential diagnosis between tuberculous meningitis (TBM) and bacterial meningitis (BM) remains challenging in clinical practice. This study aimed to establish a...
BACKGROUND
The differential diagnosis between tuberculous meningitis (TBM) and bacterial meningitis (BM) remains challenging in clinical practice. This study aimed to establish a diagnostic model that could accurately distinguish TBM from BM.
METHODS
Patients with TBM or BM were recruited between January 2017 and January 2021 at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort). The detection for indicators involved in cerebrospinal fluid (CSF) and T-SPOT assay were performed simultaneously. Multivariate logistic regression was used to create a diagnostic model.
RESULTS
A total of 174 patients (76 TBM and 98 BM) and another 105 cases (39 TBM and 66 BM) were enrolled from Qiaokou cohort and Caidian cohort, respectively. Significantly higher level of CSF lymphocyte proportion while significantly lower levels of CSF chlorine, nucleated cell count, and neutrophil proportion were observed in TBM group when comparing with those in BM group. However, receiver operating characteristic (ROC) curve analysis showed that the areas under the ROC curve (AUCs) produced by these indicators were all under 0.8. Meanwhile, tuberculosis-specific antigen/phytohemagglutinin (TBAg/PHA) ratio yielded an AUC of 0.889 (95% CI, 0.840-0.938) in distinguishing TBM from BM, with a sensitivity of 68.42% (95% CI, 57.30%-77.77%) and a specificity of 92.86% (95% CI, 85.98%-96.50%) when a cutoff value of 0.163 was used. Consequently, we successfully established a diagnostic model based on the combination of TBAg/PHA ratio, CSF chlorine, CSF nucleated cell count, and CSF lymphocyte proportion for discrimination between TBM and BM. The established model showed good performance in differentiating TBM from BM (AUC: 0.949; 95% CI, 0.921-0.978), with 81.58% (95% CI, 71.42%-88.70%) sensitivity and 91.84% (95% CI, 84.71%-95.81%) specificity. The performance of the diagnostic model obtained in Qiaokou cohort was further validated in Caidian cohort. The diagnostic model in Caidian cohort produced an AUC of 0.923 (95% CI, 0.867-0.980) with 79.49% (95% CI, 64.47%-89.22%) sensitivity and 90.91% (95% CI, 81.55%-95.77%) specificity.
CONCLUSIONS
The diagnostic model established based on the combination of four indicators had excellent utility in the discrimination between TBM and BM.
Topics: Adult; Antigens, Bacterial; Biomarkers; Cerebrospinal Fluid; China; Cohort Studies; Diagnosis, Differential; Enzyme-Linked Immunospot Assay; Female; Humans; Interferon-gamma; Male; Meningitis, Bacterial; Middle Aged; Models, Biological; Mycobacterium tuberculosis; Tuberculosis, Meningeal
PubMed: 34867952
DOI: 10.3389/fimmu.2021.731876 -
Journal of the American Association For... Nov 2019NHP are a small, but critical, portion of the animals studied in research laboratories. Many NHP are imported or raised at one facility and subsequently moved to another...
NHP are a small, but critical, portion of the animals studied in research laboratories. Many NHP are imported or raised at one facility and subsequently moved to another facility for research purposes. To improve our understanding of the effects of transportation and relocation on the NHP immune system, to minimize potential confounds associated with relocation, and to maximize study validity, we examined the phenotype and function of PBMC in cynomolgus macaques () that were transported approximately 200 miles by road from one facility to another. We evaluated the phenotype of lymphocyte subsets through flow cytometry, mitogen-specific immune responses of PBMC in vitro, and plasma levels of circulating cytokines before transportation, at approximately 24 h after arrival (day 2), and after 30 d of acclimation. Analyses of blood samples revealed that the CD3 and CD4 T-cell counts increased significantly, whereas NK, NKT, and CD14 CD16 nonclassical monocyte subsets were decreased significantly on day 2 after relocation compared with baseline. We also noted significantly increased immune cell function as indicated by mitogen-specific proliferative responses and by IFNγ levels on day 2 compared with baseline. After 30 d of acclimation, peripheral blood CD4 T-cells and monocyte counts were higher than baseline, whereas B-cell numbers were lower. The mitogen-induced responses to LPS and IFNγ production after stimulation with pokeweed mitogen or phytohemagglutinin remained significantly different from baseline. In conclusion, the effects of transportation and relocation on immune parameters in cynomolgus monkeys are significant and do not fully return to baseline values even after 30 d of acclimation.
Topics: Acclimatization; Animal Husbandry; Animals; Cytokines; Laboratory Animal Science; Macaca fascicularis; T-Lymphocyte Subsets; Transportation
PubMed: 31604484
DOI: 10.30802/AALAS-JAALAS-19-000007