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During the last decade, blood purification therapies have been proposed as an effective therapy to control the cytokines dysregulation in systemic inflammatory syndromes. Among them, the treatment with high cut-off membranes is characterized by larger pore size and more effective clearance for middle molecular weight molecules (cytokines). In this paper, we performed a thoughtful review of the literature on HCO being used for blood purification indications in all systemic inflammation syndromes. Clinical and experimental studies show that the use of high effluent flows in a pure diffusive treatment effectively removes serum cytokines with a safe profile in albumin clearance. In clinical studies, the removal of these inflammatory mediators is associated with a significant improvement in hemodynamic condition, oxygenation indices, and organ dysfunction. © 2014 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Cure of acute leukemia after transplantation is mediated by the grafted cells. We investigated the graft-versus-leukemia effect (GVL) in patients with cutaneous acute graft-versus-host disease (GVHD) treated with photochemotherapy (psoralen and ultraviolet light type A).Method: Forty-seven patients with acute leukemia were followed 5,000 days after transplantation to assess survival and GVL by multivariate analysis. The primary predictor was time to treatment of cutaneous acute GVHD by photochemotherapy separated into treatment start during the first week of acute GVHD versus after the first week of acute GVHD.Results: Photochemotherapy started after the first week of acute GVHD predicted GVL with a hazard ratio (HR) of 3.94 (95% confidence interval, CI, 1.67-9.33, p = 0.0018) and survival with preserved GVL with an HR of 2.63 (95% CI 1.30-5.32, p = 0.007). The effects on GVL and survival with preserved GVL were present regardless of whether the patients were transplanted in remission or relapse (p < 0.05). Chronic GVHD came earlier in the group that started photochemotherapy after 1 week of acute GHVD, but chronic GVHD did not increase the GVL.Conclusion: The timing of photochemotherapy after cutaneous acute GVHD may direct the GVL and predict long-term leukemia-free survival. [ABSTRACT FROM AUTHOR]

Background/Aim: Immune cells, e.g. microglial cells of the retina, appear to be involved in pathological processes in neovascular age-related macular degeneration. Therefore, the purpose of this study was to immunohistochemically check the expression of various factors and cytokines by CD11b-positive (CD11b+) immune cells in an animal model of choroidal neovascularisation (CNV). Methods: We used the animal model of laser-induced CNV in mice. Eyes were isolated at 1, 4, 7, and 14 days after laser treatment. Cryosections were prepared and checked immunohistochemically for the presence of different growth factors and cytokines on microglial cells and other immune cells identified by CD11b immunoreactivity. Results: We found that the number of CD11b+ cells at the laser spots increased dramatically 4 days after laser treatment, the majority of them entering the laser spot most probably by migration. CD11b+ cells in the laser spot were positive for a variety of pro-angiogenic factors, such as PDGF-β, FGF-1, FGF-2, and TGF-β1. They were also positive for some inflammatory cytokines, in particular TNF-α, IL-6, and CXCL1. In non-treated retinas, CD11b+ cells showed almost no immunoreactivity for these proteins. Conclusion: Microglial cells, macrophages, and other CD11b+ cells may promote the neovascularisation in the laser spot and show a moderate inflammatory behaviour. Immunoreactivity for most of these molecules was found to decrease during the time of observation. Modulation of immune cell activity may thus be a tool to reduce the extent of CNV. [ABSTRACT FROM AUTHOR]

Background/Aims: Microglia are the resident immune cells in the brain and play a pivotal role in immune surveillance in the central nervous system (CNS). Brain mast cells are activated in CNS disorders and induce the release of several mediators. Thus, brain mast cells, rather than microglia, are the "first responders" due to injury. However, the functional aspects of mast cellmicroglia interactions remain uninvestigated. Methods: Conditioned medium from activated HMC-1 cells induces microglial activation similar to co-culture of microglia with HMC-1 cells. Primary cultured microglia were examined by flow cytometry analysis and confocal microscopy. TNF- alpha and IL-6 were measured with commercial ELISA kits. Cell signalling was analysed by Western blotting. Results: In the present study, we found that the conditioned medium from activated HMC-1 cells stimulated microglial activation and the subsequent production of the pro-inflammatory factors TNF-α and IL-6. Co-culture of microglia and HMC-1 cells with corticotropin-releasing hormone (CRH) for 24, 48 and 72 hours increased TNF-α and IL-6 production. Antagonists of histamine receptor 1 (H1R), H4R, proteinase-activated receptor 2 (PAR2) or Toll-like receptor 4 (TLR4) reduced HMC-1-induced pro-inflammatory factor production and MAPK and PI3K/AKT pathway activation. Conclusions: These results imply that activated mast cells trigger microglial activation. Interactions between mast cells and microglia could constitute a new and unique therapeutic target for CNS inflammation-related diseases. [ABSTRACT FROM AUTHOR]

Herpes zoster, clinically referred to as shingles, is an acute, cutaneous viral infection caused by reactivation of the varicella zoster virus, the same virus that causes chickenpox. The incidence of herpes zoster and its complications increase with decline in cell-mediated immunity, including age-associated decline. The most effective management strategy for herpes zoster is prevention of the disease through vaccination in those who are most vulnerable. Despite the demonstrated efficacy in reducing the incidence and severity of herpes zoster, the uptake of vaccine remains low. Here, we will discuss the controversies that surround the live herpes zoster vaccine and address the common clinical questions that arise. We will also discuss the new adjuvanted herpes zoster vaccine currently under investigation. [ABSTRACT FROM AUTHOR]

Angioimmunoblastic T-cell lymphoma shows a high release of cytokines. Different blood purification techniques are employed to control hypercytokinemia. Here we investigated the effects of intermittent supra-hemodiafiltration with endogenous reinfusion on cytokine removal in a patient presenting with acute kidney injury. After the first day of chemotherapy for angioimmunoblastic T-cell lymphoma, a 78-year-old male patient developed acute kidney injury and systemic inflammatory response syndrome due to massive release of inflammatory cytokines. Three sessions of supra-hemodiafiltration were performed. Blood samples for evaluation of renal function and inflammatory mediators were collected at the beginning and the end of each dialytic session. A marked improvement of clinical state and renal function was associated to a significant reduction of inflammatory markers. Our results suggest that renal replacement therapy with supra-hemodiafiltration may remove a wide spectrum of inflammatory mediators and uremic toxins involved in acute kidney injury and systemic inflammatory response syndrome. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aim: The role of Th2-type cytokines in development of eosinophilic esophagitis (EoE) has been largely revealed, whereas research on the pathogenesis of eosinophilic gastroenteritis (EGE) has not been widely performed. We investigated the possible involvement of Th2-type cytokines in EGE by measuring plasma cytokine concentrations in patients with EGE as well as those with EoE. Methods: 18 patients with EoE, 18 with EGE, and 30 normal volunteers were enrolled in the study. Plasma concentrations of five cytokines (thymic stromal lymphopoietin, IL-5, IL-13, IL-15, and eotaxin-3) were measured using Milliplex® assays. Clinical characteristics of the patients and plasma cytokine levels were then compared. Results: Higher proportions of patients with EoE and those with EGE showed elevated plasma concentrations of IL-5 and IL-15 as compared to the normal controls. There was also a positive correlation between IL-5 and IL-15, and also with blood eosinophil count. The plasma concentrations of these cytokines tended to be higher in cases with EGE than in those with EoE, though there were overlaps in cytokine levels among the patients and controls. Conclusion: Similar increases in plasma IL-5 and IL-15 were observed in patients with EoE and those with EGE. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Depression is an inflammatory disorder while many authors declare myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) to be a functional disorder. The aim of the present study is to compare inflammatory and cell-mediated immune (CMI) responses between depression and ME/CFS. Methods: We measured two proinflammatory cytokines (PICs) in plasma, interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), with enzyme-linked immunosorbent assays, and serum neopterin with a radioimmunoassay in controls, ME/CFS and depressive patients. Results: Plasma PICs were significantly higher in ME/CFS than in depression and higher in both patient groups than in controls. Increased PIC levels in depression were attributable to the presence of fatigue and physio-somatic symptoms. Serum neopterin did not differ significantly between depression and ME/CFS but was higher in both patient groups than in controls. The significant positive correlations between neopterin and either IL-1 or TNF-α were significantly greater in depression than in ME/CFS. Conclusions: Since PICs cause depression-like behaviors and fatigue/malaise, we suggest that inflammation may play a role in the pathophysiology of ME/CFS and depression. Increased neopterin also seems to contribute to the pathophysiology of both disorders. This study has detected a shared 'pathway phenotype', i.e. disorders in inflammatory and CMI pathways, which underpins both ME/CFS and depression and, therefore, may explain the co-occurrence of both disorders. ME/CFS and depression are discriminated from each other by increased PICs in ME/CFS and differences in the immune cell communication networks. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: The NFAT family transcription factors play crucial roles in T cell functions. Recently, NFAT has been implicated in the production of an inflammatory cytokine, IL-17A; however, functional differences among NFAT members in IL-17A synthesis have not been elucidated. In this study, the relative contribution of NFAT1 and NFAT2 to IL-17A expression in human T cells was investigated. Methods: NFAT1 and NFAT2 were introduced in human cord blood CD4+ T cells by a lentiviral transduction system. Then, the expression of IL-17A mRNA was determined by quantitative real-time RT-PCR. The transient effects of NFAT1 and NFAT2 on IL-17A expression in Jurkat-Tag cells were also investigated. Results: Stimulation-induced expression of IL-17A in human CD4+ T cells was augmented by the introduction of NFAT1 and more vigorously, NFAT2. IL-17A expression in Jurkat-Tag cells was also enhanced by NFAT1, whereas it was not affected by NFAT2. Conclusion: NFAT1 and NFAT2 facilitated IL-17A expression in human T cells, though distinct mechanisms might be involved in these effects. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Lacrimal gland enlargement (LGE) is one of the characteristics of Mikulicz's disease (MD). Recently, marked serum immunoglobulin (Ig)G4 elevation and infiltration of IgG4-positive plasma cells in the enlarged exocrine glands have been reported in MD patients. Moreover, we have reported that in patients with LGE and elevated serum IgG4 levels (IgG4-related LGE), T helper type 2 (Th2) cell-mediated immune responses are enhanced. Although prostaglandin D2 (PGD2) and its receptor CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) have been shown to be involved in Th2 cell-related diseases such as bronchial asthma, their roles in IgG4-related diseases remain unknown. Aim: The aim of this study is to address the role of CD4+ T cells expressing CRTH2 (CRTH2+ CD4+ T cells) in IgG4-related LGE. Methods: We examined the expression of CCR4, CXCR3 and CRTH2 on peripheral blood CD4+ T cells in patients with IgG4-related LGE, in patients with bronchial asthma and in healthy controls. Results: The ratio of CCR4+ to CXCR3+ in CD45RO+ CD4+ T cells was increased in patients with IgG4-related LGE when compared to that in healthy controls, confirming that Th2 cells are predominant in patients with IgG4-related LGE. In addition, the frequency of CRTH2+ cells in CD4+ T cells was significantly increased in these patients, compared to healthy controls. Furthermore, although not statistically significant, the frequency of CRTH2+ cells in CD4+ T cells tended to correlate with the levels of serum IgE and the number of blood eosinophils in patients with IgG4-related LGE. Conclusion: CRTH2+ CD4+ T cells may be involved in the pathogenesis of IgG4-related LGE. Copyright © 2012 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Human papillomavirus (HPV) oncoproteins (i.e. E6 and E7) are constitutively expressed in cervical cancer cells. The proteins are ideal targets to be used for developing therapeutic vaccines against existing HPV-associated carcinomas. To date, whole bacteriophage ('phage')-λ particles, rather than purified 'naked' DNA, have been described as highly efficient delivery vehicles for a DNA vaccine. Methods: In this study, a safe and efficient λ-based therapeutic cancer vaccine, recombinant λ-ZAP E7 phage, was developed by inserting a HPV16 E7 gene into the Lambda ZAP® cytomegalovirus vector. λ-ZAP E7 phages were employed to immunize mice against the E7-expressing murine tumor cell line (TC-1), which is used as a tumor model in an H-2b murine system. Results: The tumor-bearing mice indicated a significant inhibition of tumor growth after 3 injections of 2 × 1012 particles of recombinant phages. Released lactate dehydrogenase, interferon-γ and granzyme B from spleen cells and lymphocyte proliferation of spleen cells, which all demonstrate the enhancement of cell-mediated immunity, suggested the phages could be a potent gene delivery system in animal models. Conclusion: Our results suggest the recombinant phages can be used as effective biological tools for inducing E7-specific protective immune responses. Hence, the study introduces a possible therapeutic strategy against cervical cancer and other HPV-related neoplasia. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: An increased percentage of pro-inflammatory CD14+CD16+ monocytes might contribute to inflammation in hemodialysis (HD) patients. The purpose of the study was to evaluate the possible contribution of pro-inflammatory monocytes to inflammation in HD patients and also to evaluate the effect of on-line hemodiafiltration (HDF). Methods: Flow cytometric detection of monocytes in patients undergoing HD, on-line HDF and healthy controls as well as plasma cytokines and cytokine mRNA measurement were performed. Results: Percent pro-inflammatory monocytes, plasma cytokines and cytokine mRNA significantly increased in HD patients. Intracellular cytokine staining showed pro-inflammatory monocytes were the predominant source of tumor necrosis factor-α. Percent pro-inflammatory monocytes positively correlated with plasma inflammatory cytokines. Percent pro-inflammatory monocytes, plasma cytokines and cytokine mRNA significantly decreased in on-line HDF patients. Conclusion: Increased pro-inflammatory monocytes are likely to contribute to inflammation in HD patients, and beneficial effect of on-line HDF might be partially mediated by modulating the inflammatory response. Copyright © 2011 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The article discusses a study on the differences between the regulatory and pro inflammatory cytokine responses to toll-like receptors (TLR)-1-6 stimulation of cord blood vessels of neonates and adults. The study used a variety of TLR ligands, which include zymosan, flagellin and Pam3CSK4. It aims to determine the role of TLR in the immune response of neonates.

Background: Functional alterations of innate lymphocytes, which can mount rapid immune responses and shape subsequent T cell reactions, were examined in the acute phase of ischemic stroke. Methods: Frequencies, intracellular perforin and interferon-γ (IFN-γ) expression of Vδ2 T cells, CD3+ CD56+ natural killer T (NKT)-like and NK cells were examined in the peripheral blood of 20 healthy controls and 28 patients within 6 h of the onset of acute ischemic stroke and after 72 h by flow cytometry. Cytokine production of isolated NKT-like and NK cells following in vitro activation was measured by cytometric bead array. NK cytotoxicity was examined in the peripheral blood mononuclear cells. Results: Percentages of Vδ2, NKT-like and NK cells were constant, and similar to percentages in healthy subjects. In contrast, proinflammatory intracellularIFN-γ expression by Vδ2 T cells, NKT-like cells and NK cells and IFN-γ production by isolated NK cells in culture was low at 6 h and reached the level of healthy subjects by 72 h after stroke. Production of anti-inflammatory cytokines was unaltered. Intracellular perforin expression by Vδ2 T cells, NKT-like cells and NK cells, and NK cytotoxicity was low at 6 h, and reached the level of healthy subjects by 72 h. Increases in IFN-γ and perforin expression by Vδ2 T cells correlated with clinical improvement indicated by decreases in NIHSS scores. Conclusions: Pro-inflammatory and cytotoxic responses of NK, NKT-like and Vδ2 T cells become acutely deficient in ischemic stroke, which may contribute to an increased susceptibility to infections. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: This study was conducted to compare the differences in adipocytokines and fatty acid composition between two fraction sizes of small and large cells from subcutaneous and visceral fat of mice receiving a high-fat diet (HFD). Methods: Body weight, blood glucose and cholesterol levels, and adipocyte diameter distribution were examined. Total adipocyte fractions could be separated into the small-cell fraction (SCF) and the large-cell fraction (LCF). Adipocytokine expression, fatty acid composition and stearoyl-CoA desaturase (SCD) expression were compared between SCF and LCF. Results: In HFD mice, body weight, glucose and cholesterol levels were significantly higher than in NCD mice. The adipocyte diameter of HFD mice continuously increased throughout the feeding period regardless of the fat depot. The expression of adipocytokine genes such as angiotensinogen, plasminogen activator inhibitor-1, adipsin, leptin, TNF-α and adiponectin was higher in LCF than SCF. The ratio of stearic acid to the total fatty acid content was lower in SCF than LCF, whereas oleic acid composition was higher in LCF. SCD expression was higher in LCF than SCF. Conclusion: Our results indicate that large adipocytes strongly express adipocytokine genes and show high oleic acid composition via SCD upregulation. Based on these findings, the differences in fatty acid composition between adipocyte sizes may be related to adipocytokine expression. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Epigallocatechin-3-O-gallate (EGCG), the main catechin in green tea, has anti-oxidant, anti-atherosclerotic and anti-inflammatory properties. Fractalkine, a chemokine involved in inflammation and early atherosclerotic processes, acts as a chemoattractant as well as an adhesion molecule in endothelial cells activated by proinflammatory cytokines. In the present study, we investigated the effect of EGCG on fractalkine expression in TNF-α-induced human umbilical vein endothelial cells (HUVECs). EGCG decreased TNF-α-induced fractalkine mRNA and protein expression in HUVECs in a time-dependent manner. EGCG suppressed the TNF-α-induced phosphorylation and degradation of IκB-α, thereby decreasing the phosphorylation and nuclear translocation of the NF-κB p65 subunit in HUVECs. The DNA binding activity of the NF-κB p65 subunit was lower in EGCG-pretreated HUVECs than in those treated with TNF-α alone. Furthermore, EGCG inhibited monocyte adhesion to HUVECs stimulated by TNF-α. The silencing of fractalkine with an siRNA or treatment with a blocking antibody against fractalkine suppressed the TNF-α-induced increase in monocyte adhesion. These results demonstrate that EGCG prevents TNF-α-induced vascular endothelial fractalkine expression. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

CC chemokine receptor 4 (CCR4) is expressed on Th2 cells, found in inflamed tissues of allergic diseases, and is therefore suspected to be involved in the pathogenesis of allergic diseases by controlling Th2 cell migration into inflamed tissues. The aim of the present study was to investigate the inhibitory effect of a selective CCR4 antagonist, K327 [6-cyclopropancarbonyl-4-(2,4-dichlorobenzylamino)-2-(4-[2-(piperidin-1-yl)ethyl] piperazin-1-yl)-7,8-dihydro-5H-pyrido (4,3-d)pyrimidine], on the recruitment of CCR4+CD4+ T cells to the airway of mice with ovalbumin-induced allergic airway inflammation. K327 was administered to mice in which CCR4+CD4+ T cell accumulation was elicited by multiple inhalations of aerosolized ovalbumin. K327 significantly and dose-dependently inhibited the recruitment of CCR4+CD4+ T cells with an ID50 value of 44 mg/kg, p.o. twice daily. The antiasthmatic potential of K327 was also demonstrated by the fact that K327 suppressed the elevation of Th2 cytokines and airway eosinophilia. These results indicate that CCR4 antagonists can control in vivo migration of Th2 cells which express CCR4 and, presumably, serve as a new class of therapeutic agent for allergy. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Aim: In this study, we tested the impact of short-term intake of increased amounts of C18:1 trans fatty acids (TFAs) on parameters of cellular and humoral immunity in healthy young men. Methods: Twenty-seven healthy young men were subsequently exposed to a standard diet for 7 days and an experimental TFA-enriched diet for 4 days. The mean energy content of these diets was 2,453 and 2,455 kcal/day, with 10, 35 and 55% of energy from proteins, fats and carbohydrates, respectively. Standard diet contained about 0.8 g and experimental diet 10.4 g TFAs. Plasma levels of C18:1 TFAs and immunological parameters were measured. Results: The 4-day increased consumption of C18:1 TFAs led to a significant decrease in mitogen-induced CD69 expression on CD8+ T cells as well as decreased phagocytic activity on neutrophils. After returning to the participants’ habitual diet (1 week after the end of the experimental diet), we observed a significant decrease in the mean level of circulating immune complexes. Concentrations of plasma immunoglobulins remained unchanged throughout the study. Conclusions: Acute impact of higher dietary C18:1 TFA intake on phagocytosis and cell-mediated immunity seems to be suppressive. This finding differs from results describing proinflammatory effects associated with long-term exposure to TFAs. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: To evaluate cell-mediated immune (CMI) response in diabetic and non-diabetic tuberculosis (TB) patients and healthy subjects in response to complex, fractionated and single antigens of Mycobacteriumtuberculosis. Material and Methods: Peripheral blood mononuclear cells (PBMC) were obtained from patients suffering from pulmonary TB and type II diabetes (n = 7), pulmonary TB without diabetes (n = 10) and healthy subjects without TB and diabetes (n = 10). PBMC were assessed for CMI responses in antigen-induced proliferation assays in response to complex mycobacterial antigens (whole cells, cell walls and culture filtrate of M. tuberculosis), a battery of naturally purified or recombinant produced secreted (ESAT6, MPT59, MPT64 and MTB38) and cytosolic (MTB10, MTB70, ML10, ML28, ML36, ML65 and MB65) mycobacterial antigens and fractionated culture filtrate proteins (fractions F1–F10) of M. tuberculosis. Results:The majority (>70%) of diabetic and non-diabetic TB patients and healthy subjects responded to the complex antigens of M. tuberculosis. However, among the single antigens, ESAT6 was most frequently recognized by TB patients with and without diabetes, but least recognized by healthy subjects. The secreted antigens MPT59 and MPT64 were recognized by all the groups, whereas the cytosolic antigens were recognized best by healthy subjects. When tested with fractionated secreted proteins present in the culture filtrate of M. tuberculosis, the best responses in both diabetic and non-diabetic TB patients were obtained with fractions containing low-molecular-weight proteins. Conclusions: Diabetic and non-diabetic TB patients respond frequently to secreted low-molecular-weight ESAT6 antigen of M. tuberculosis, indicating that this antigen may be useful in the diagnosis of TB in both the groups. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

AbstractBackground:The rate of caesarean deliveries has increased 10-fold worldwide during the past decades. Objective:To evaluate differences in the establishment of gut microbiota in infants born by vaginal or caesarean delivery and its impact on mucosal immunity. Methods:Altogether, 165 consecutive children, prospectively followed from birth at our clinic in Turku, Finland, were gathered; 141 (85) were born by vaginal delivery and 24 (15) by caesarean section. Blood was drawn at physician visits for indirect evaluation of mucosal immunity by ELISPOT assay. Faecal samples were obtained for determination of the gut microbiota by fluorescence in situ hybridization of bacterial cells. Results:Infants delivered by caesarean section harboured fewer bifidobacteria at an early age and were shown to mount a stronger humoral immune response. At 1 month of age, the total gut bacterial cell counts per 1 g faeces were higher in vaginally delivered infants (9.9 × 109, 95 CI 7.9 × 109–1.2 × 1010) as compared to caesarean section delivered (3.1 × 109, 95 CI 1.1 × 109–8.6 × 109) (p = 0.001). This distinction was mainly due to the greater number of bifidobacteria in vaginally delivered infants (1.9 × 109, 95 CI 6.3 × 108–5.6 × 109vs. 1.5 × 106, 95 CI 4.1 × 102–5.7 × 109, respectively) (p = 0.001). During the first year of life, the total number of IgA-, IgG- and IgM-secreting cells was lower (p = 0.03, p = 0.02, p = 0.11, respectively) in infants born by vaginal delivery than in those born by caesarean section, possibly reflecting excessive antigen exposure across the vulnerable gut barrier. Conclusions:Our findings demonstrate that the mode of delivery may have, possibly via gut microbiota development, significant effects on immunological functions in the infant (http://www.clinicaltrials.gov/ct/gui/show/NCT00167700).Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Evans syndrome (ES) is a rare disorder characterized by combined autoimmune thrombocytopenia and autoimmune hemolytic anemia. Several studies have documented a number of B cell defects, whereas only limited information is currently available about the T cell subset. Methods: A wide panel of immunological analyses aiming specifically at a quantitative and qualitative evaluation of the T cell compartment was performed in an unusual case of ES. The peripheral distribution of the T cell subsets, the diversity of the T cell receptor (TCR) repertoires, the cytokine profile and the T cell apoptosis have been longitudinally evaluated. Results: On first investigation, flow-cytometric immunophenotyping showed a remarkable alteration of T cell homeostasis with deeply reduced CD4+ naive T cells and recent thymic emigrants. This was seen in association with increased levels of T cell activation and apoptosis. Consistently with these data the cytokine profile was characterized by high interferon-γ and low interleukin-2 levels. Staining for CD4 and CD25 molecules showed decreased percentages of circulating regulatory T cells according to the autoimmune nature of ES. Finally, restricted TCR repertoires were demonstrated by a skewed TCR β chain variable (TCRBV) gene usage as well as oligoclonal third complementarity- determining region (CDR3) profiles. A deterioration of the above-mentioned parameters and a worsening of the clinical condition were observed during the follow-up requiring more intensive treatments. Conclusion: The demonstration of multiple T cell defects, in addition to providing pathogenetic information, is likely to alter both acute treatment and outcome of ES. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

T cell differentiation, which leads to the generation of Th cells with a characteristic cytokine expression pattern, is regulated by diverse factors. In addition to the cytokine environment, the cellular redox status often serves as an important factor in survival and differentiation of Th cells. Thioredoxin, an intracellular redox sensor protein, has been suggested in the induction of Th1 response through the production of IL-12 by monocytes. Here we report that thioredoxin expression is up-regulated by IFN-γ and other Th1 type cytokines in human primary immune cells, and that the overexpression of thioredoxin resulted in a specific increase in the mRNA level and promoter activity of IFN-γ in mitogen-stimulated Jurkat T cells. Using the active site mutant (C32S/C35S) of thioredoxin, we demonstrate that such IFN-γ-inducing capacity of thioredoxin is dependent on the redox-sensing activity of thioredoxin and involves the activation of transcription factors such as NF-κB and Stat1. Together, the results of the present study suggest that thioredoxin is a direct stimulator of IFN-γ gene expression in human T cells and that there is a positive feed-back circuit by IFN-γ and thioredoxin in the regulation of Th1 immune response. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Cytokine overproduction has been noted during the aggravation of clinical conditions. Countermeasures to control hypercytokinemia are therefore important in critical care. We investigated the clinical efficacy of hemoadsorption therapy using a new cytokine-adsorbing device in critically ill patients with persistent or severe hypercytokinemia. Methods: Direct hemoperfusion using the CYT-860, a cytokine-adsorber column (CYT-860-DHP), was performed in critically ill patients with hypercytokinemia. To evaluate the efficacy of CYT-860-DHP, changes in pathological and clinical parameters were examined. Results: Seven patients with hypercytokinemia and a SOFA score of ≥5 underwent CYT-860-DHP treatment. Four patients survived 28 days after CYT-860-DHP treatment. Significant decreases in blood levels of cytokines were observed. PaO2/FIO2 improved significantly. Conclusion: The possibility that CYT-860-DHP treatment can reduce blood cytokine levels and thereby improve the general condition of patients was suggested. These findings warrant the initiation of a prospective randomized trial to evaluate the clinical efficacy of CYT-860-DHP treatment. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

A growing body of evidence suggests that changes in the serum levels and cellular production of various cytokines are associated with the immunological abnormalities of schizophrenia. Several studies have examined alterations in T helper type 1 (Th1) and T helper type 2 (Th2) cytokines in schizophrenia. We explored monocytic, Th1 and Th2 cytokines in 43 schizophrenia patients and 50 normal controls. The mitogen-induced production of tumor necrosis factor α (TNF-α), interleukin 6 (IL-6), IL-4, γ-interferon (IFN-γ) and IL-2 was measured with enzyme-linked immunosorbent assays before and after antipsychotic treatment. IL-6 and TNF-α production by schizophrenic patients was significantly higher than by normal controls, while IL-2, IL-4 and IFN-γ production was significantly lower in schizophrenic patients. After 6 weeks of antipsychotic treatment, IL-6 and TNF-α production was significantly decreased, while IL-4, IFN-γ and IL-2 productions were not significantly changed. Our results suggest that increased monocytic cytokines and decreased Th1 and Th2 cytokines may be associated with the immunopathogenesis of acute psychotic schizophrenia, and that antipsychotics may play an important role in immune response by decreasing elevated monocytic cytokines. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aim: Epidemiological studies have suggested that moderate alcohol consumption is associated with lower morbidity. However, intervention studies are needed to elucidate mechanisms involved. This study was aimed to determine the effects of moderate beer consumption on the immune function of healthy adults, taking into account gender differences. Methods: After a 30-day alcohol abstinence period, 57 healthy volunteers consumed a moderate intake of beer (330 ml for women and 660 ml for men) for 30 days. Total leukocyte and lymphocyte counts; absolute values of T-lymphocyte CD3+, CD4+, and CD8+ subsets; delayed-hypersensitivity skin response (DHSR); absolute values of B lymphocytes (CD19+) and serum immunoglobulin concentrations (IgG, IgA, and IgM); and cytokine production (IL-2, IL-4, IL-6, IL-10, IFN-γ, and TNF-α) were evaluated following the abstinence and alcohol consumption periods. Results: After moderate beer consumption CD3+ cells increased only in women (p < 0.05). IgG, IgM, and IgA concentrations, as well as IL-2, IL-4, IL-10, and IFN-γ cytokine production increased while IFN-γ/IL-10 ratio decreased in both men and women (p < 0.05). The rest of the immunological parameters analyzed remained unchanged. Conclusion: Moderate beer consumption produced an immunomodulatory effect in a healthy adult Spanish population; this effect appears to be more relevant in women than in men. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The placenta is an attractive new source of mesenchymal stem cells (MSCs), but the biological characteristics of placenta-derived MSCs (P-MSCs) have not yet been characterized. We successfully isolated, cultured and expanded P-MSCs using routine methods. Under appropriate induction conditions, these cells can differentiate into bone, cartilage, fat and hepatocyte-like cells. In addition, the proliferative response of P-MSCs to different cytokines was monitored using the MTT assay. The results show that low concentrations of proinflammatory cytokines, e.g. RANTES, interleukin (IL)-1, IL-6 and IL-8 can stimulate the proliferation of P-MSCs in a dose-dependent manner, peaking at concentrations of 40 ng/ml of RANTES, 10 ng/ml of IL-1 and IL-6, and 150 ng/ml of IL-8 (p < 0.01). The level of proliferation decreased when the concentration of these four cytokines increased beyond these values. On the other hand, anti-inflammatory cytokines hepatocyte growth factor and IL-4 had an inhibitory effect on P-MSCs. In conclusion, the placenta contains MSCs that are consistent with the characteristics of bone marrow MSCs. Low concentrations of proinflammatory chemokines stimulated the proliferation of P-MSCs while anti-inflammatory cytokines inhibited the growth of P-MSCs in a dose-dependent manner. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Previously reported increased lymphocyte proliferative responses in cow’s milk allergy (CMA) may have been influenced by the lipopolysaccharides (LPS) which contaminate most commercial cow’s milk protein (CMPs). Moreover, peripheral blood mononuclear cells (PBMC) contain both B cells, CD45RA+ naïve T cells, CD25+ regulatory T cells (Tregs) in addition to antigen-specific CD45RA– memory T cells. Methods: PBMC from clinically reactive and tolerised patients with IgE- and non-IgE-mediated CMA were depleted of CD45RA+ T cells and putative CD25+ Tregs. The proliferative index to LPS-depleted α-, β- and κ-casein and β-lactoglobulin was compared in the memory T-cell-enriched, Treg-depleted PBMC and in bulk PBMC. Results: Clinically reactive IgE-mediated CMA patients had increased responses to caseins only. Tolerised patients, particularly those with atopic dermatitis, had decreased responses to κ-casein which were restored after Treg depletion. Interleukin-4 and interferon-γ were generally not detected in the culture supernatants. No differences were seen between reactive and tolerant delayed non-IgE-mediated CMA patients. Conclusions: Proliferative responses to α-, β- and κ-caseins (but not β-lactoglobulin) were observed in clinically reactive IgE-mediated CMA patients only. A markedly decreased proliferative response to κ-casein in tolerised IgE-mediated CMA patients with atopic dermatitis, which was abrogated by Treg depletion, suggested a role for κ-casein in tolerance induction. Non-IgE-mediated CMA patients had no increased proliferative response to any milk proteins. Copyright © 2007 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Limiting allergen exposure in the sensitization phase has been proposed as a means of primary prevention of asthma, but its effectiveness is debated. Hypothesis: Primary prevention of asthma is more effective in limiting asthma symptoms in young guinea pigs compared with adults, whether males or females. Methods: The following experimental groups were used: young/young, sensitized and challenged before sexual maturity; young/adult, sensitized young and challenged after sexual maturity; adult/adult, sensitized and challenged after sexual maturity. Males and females were sensitized intraperitoneally with varying doses of ovalbumin (OVA) and challenged intratracheally with a constant OVA dose. Cellular infiltration into lung and lavage fluid as well as airway hyperresponsiveness to intravenous methacholine was determined 24 h later. Results: In unsensitized animals, density of resident inflammatory cells as well as baseline pulmonary function differed with age and sex. Maximum OVA-induced eosinophilia in females occurred at a lower sensitizing dose of OVA than in males, and the slopes of the dose-response relationship differed significantly between sexes. Young females had more pronounced increases in eosinophils compared with some adult treatment groups. The concentrations of OVA-specific antibodies were not directly related to differences in cellular infiltration. Airway hyperresponsiveness to methacholine challenge was observed in all treatment groups. Conclusion: Young animals require major reductions in allergen exposure compared with adults to effectively limit airway inflammation in primary prevention. Heterogeneity of asthma symptoms seen with age and sex suggests that primary prevention by limiting allergen exposure or treatment with anti-inflammatory or bronchodilator drugs may be more effective strategies for specific age and gender populations. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: The aim of this work was to study the effects of daily yogurt consumption on the cellular immunity of young healthy women and to compare a conventional with a probiotic product. Methods: 33 young healthy women (22–29 years) consumed 100 g/day of either probiotic or conventional commercially available yogurt for 2 weeks and 200 g/day for another 2 weeks followed by a 2-week washout period with no fermented food at all. Before the intervention and after each phase, a complete white blood count was done, the percentage of activated CD69+ T lymphocytes after stimulation of whole blood with pokeweed mitogen was determined as well as the natural cytotoxicity of peripheral blood mononuclear cells against a human erythroleukemic target cell line (K562). All analyses were done by flow cytometry. Results: In the probiotic group only, the numbers of cytotoxic T lymphocytes (CD3+CD16+CD56+) increased significantly (+30.8% with p = 0.001, +22.1 and +32.7% with p = 0.002, for T2, T3 and T4 compared to T1). There were no major changes for other cell populations, and all remained within the physiological range. In both groups, the expression of CD69 on T lymphocytes increased after yogurt consumption, especially on CD8+ (conventional: T2 +23%, T3 +27.2%, probiotic: T2 +15.7%; T3 +10.8% compared to T1) and to a lesser extent on CD4+ (conventional: T2 +7.7%, T3 +14.9%, probiotic: T2 +4% compared to T1. The cytotoxic activity also augmented following the intake, this effect persisting after cessation of consumption. However, there were no significant differences between the probiotic and the conventional yogurt group. Conclusion: Daily yogurt intake has a stimulating effect on cellular immune functions, but in this study the probiotic product did not perform better than the traditional one. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Asthma is a chronic inflammatory disease of the airways. Mast-cell (MC)-derived cytokines may mediate both airway inflammation and remodeling. It has also been shown that airway smooth muscle cells (ASMC) can be a source of proinflammatory cytokines. In the human airways, MC-ASMC cell interactions may have pivotal effects on modulating inflammation. Objectives: We wanted to know whether the production of eotaxin, an important proinflammatory cytokine, through a cell-to-cell contact mechanism of human ASMC activation by MC was mediated by p38 MAPK. Methods: We cocultured normal humanASMC with a human MC line (HMC-1) and assayed for the production of eotaxin. Results: When cultured together, human ASMC and HMC-1 contact induced eotaxin secretion. Separation of HMC-1 and human ASMC by a porous membrane inhibited this induction. Coculturing of human ASMC with HMC-1 induced increased expression of eotaxin gene mRNA. HMC-1-derived cellular membranes caused an increase in eotaxin production in human ASMC. Activation of p38 MAPK was also seen in cocultures by Western blot, whereas eotaxin production in cocultures was significantly inhibited by the p38 inhibitor SB203580. Conclusion: These novel studies reveal the importance of cell-to-cell interactions in the complex milieu of airway inflammation. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Chronic obstructive pulmonary disease (COPD) is no longer seen as a pulmonary disease, but is increasingly associated with systemic effects with important clinical relevance. Systemic immunological changes in COPD patients are characterized by an increased number of circulating inflammatory cells, functional changes of the inflammatory cells, elevated plasma levels of cytokines, and oxidative stress. Physical exercise induces an abnormal systemic inflammatory and oxidative response in COPD patients, which is seen in both the circulation and the peripheral muscles. Although mechanisms and consequences of these effects are not yet fully understood, they could be harmful in COPD patients by inducing damage or functional changes in, for example, skeletal muscles. Whether these changes of the immune system can also affect the susceptibility to infections in these patients is unknown. The concept of COPD as a systemic rather than only a pulmonary disease also opens new perspectives on the development for new therapeutic interventions. The effects of new antioxidative and anti-inflammatory agents are investigated. A better understanding of the complexity of the systemic effects will aid the development of new therapies and management strategies for patients with COPD. Copyright © 2006 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Mast cells are key effector cells in the early-phase allergic inflammation and in diverse immunological and pathological processes. Sopoongsan (SPS), a traditional Korean medicine, has been used as therapeutics for allergic diseases such as atopic dermatitis (AD). The precise effect in experimental models of SPS, how-ever, remains unknown. In this report, we investigated the effect of SPS on mast cell-mediated anaphylactic reactions and cytokine production in in vivo and in vitro murine models. Methods: Compound 48/80-induced histamine and ear swelling were measured with the various concentrations of SPS. The amount of dye was determined colorimetrically after antidinitrophenyl IgE antibody-induced passive cutaneous anaphylaxis reaction. Secretion of tumor necrosis factor-α (TNF-α), interleukin-8 (IL-8) and IL-6 in supernatants from HMC-1 cells was measured by a sandwich enzyme-linked immunosorbent assay. The expression level of nuclearfactor (NF)-κB/Rel A in the nucleus and the activation of mitogen-activated protein kinases (MAPKs) were examined by Western blot analysis. Results: SPS inhibited the degranulation and histamine release from the rat peritoneal mast cells activated by compound 48/80. Compound 48/80-induced ear swelling was significantly reduced. SPS also showed an inhibitory effect of passive cutaneous anaphylaxis reaction. Significantly reduced levels (p < 0.05) of TNF-α, IL-8 and IL-6 were observed in the human mast cell line with SPS and SPS components. In addition, SPS inhibited an increase of NF-κB and extracellular signal-regulated kinase ½ activity. Conclusions: These findings suggest that SPS has an inhibitory effect on atopic allergic reaction and this might be useful for the clinical application to treat allergic diseases such as AD. [ABSTRACT FROM AUTHOR]

Background/Aim: End-stage renal disease (ESRD) induces a clinical state of immunodeficiency with a higher incidence of infections and higher mortality due to infectious complications compared with the normal population. The definite mechanism responsible for the host defense alterations is not well understood. The aim of the study was to investigate intracellularly the relationship between cytokine synthesis and oxidative stress in peripheral blood lymphocytes in children with ESRD. Methods: Twenty-one children (age 11.7 ± 5.8 years) with ESRD treated with hemodialysis (HD; n = 10) and peritoneal dialysis (PD; n = 11) were studied. Nine healthy children of comparable age formed the control group. To determine intracellular oxidative stress we used dihydrorhodamine-123 (DHR), which after oxidation to rhodamine-123 (RHO) emitted a bright fluorescent signal. Intracellular oxidation of DHR in T lymphocytes reflected intracellular oxidative stress. The intracellular synthesis of cytokines (IL-2, IFN-γ, IL-4, IL-6) was also measured. Both parameters were detected at a single-cell level by flow cytometry. Lymphocyte subsets were evaluated using the monoclonal antibodies conjugated with fluorochromes. Results: We found that in T lymphocytes the mean fluorescence intensity (MFI), which reflected intracellular oxidative stress, was increased in ESRD patients compared to the controls (CD3+: 34.77 ± 11.55 vs. 22.55 ± 4.97, p < 0.01; CD3+CD8+: 34.31 ± 12.17 vs. 20.77 ± 4.89, p < 0.01; CD3+CD4+: 36.06 ± 6.98 vs. 24.44 ± 7.68, p < 0.001). HD patients showed slightly higher MFI compared to PD patients in CD3+ cells (39.32 ± 11.70 vs. 30.63 ± 10.20, NS), in CD3+CD8+ cells (37.90 ± 14.32 vs. 31.06 ± 9.34, NS) and in CD3+CD4+ cells (40.10 ± 2.28 vs. 29.33 ± 7.06, p < 0.001). The intracellular synthesis of IL-2 was higher in ESRD patients compared to the controls, both in CD3+ cells (31.34 ± 9.80 vs. 20.49 ± 15.26%, p < 0.05) and in CD3+CD4+ cells (36.10 ± 8.69 vs. 24.03 ± 16.95%, p < 0.05). The intracellular synthesis of IFN-γ, IL-4 and IL-6 was significantly lower in the ESRD group compared to the controls. Interestingly, in patients treated with HD, negative correlations between the degree of intracellular oxidative stress and intracellular cytokine synthesis in CD3+ lymphocytes were found. Conclusion: Our results show that patients with ESRD, especially those treated with HD, present increased oxidative stress in T lymphocytes, which may lead to decreased cytokine synthesis and abnormal immune response. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Recently, recombinant hypoallergenic derivatives of the major birch pollen allergen, Bet v 1, were used to treat birch-pollen-allergic patients in a double-blind, placebo-controlled, multi-centre immunotherapy study. The aim of this study was to evaluate the effects of vaccination with aluminium-hydroxide-adsorbed recombinant Bet v 1 derivatives versus placebo on T-cell, cytokine and antibody responses in a subgroup of patients. Methods: Blood was drawn from patients of the Swedish centre (n = 27; rBet v 1 fragments: n = 10; rBet v 1 trimer: n = 8, and placebo-aluminium hydroxide: n = 9) before the start and after completion of the treatment. PBMC were stimulated with rBet v 1 and analysed for cytokine (IL-4, IL-5, IL-10, IL-12, IL-13 and IFN-γ)-secreting cells by ELISpot. Bet v 1-specific antibody levels in serum (IgG1–4, IgE and IgA) were measured by ELISA. Skin prick tests with defined Bet v 1 concentrations were performed before and 10–11 months after the beginning of the study. Results: Bet v 1-specific IgG levels, consisting of IgG1, IgG2 and IgG4, were significantly increased after treatment with recombinant allergen derivatives. Treatment with rBet v 1 trimer led to a significant (p < 0.05) reduction of Bet v 1-reactive IL-5- and IL-13-producing cells, reflecting a reduced Th2 response. In addition, a decreased number of Bet v 1-reactive IL-4 producing (p = 0.07) and an increase of IL-12-producing (p = 0.06) cells was noted in the trimer-treated patients. In contrast to placebo, active treatment resulted in significantly reduced immediate-type skin reactions to Bet v 1 even 10–11 months after treatment. Conclusion: Vaccination with recombinant hypoallergenic Bet v 1 derivatives induces a Bet v 1-specific IgG response and leads to reduced skin reactivity in allergic patients. A reduction of Bet v 1-specific Th2 responses was observed in trimer-treated patients, which may reflect the intrinsic property of this allergen derivative. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Whereas a primary role of interleukin-1β (IL-1β) in local bone remodelling and articular inflammation has been well established, the effect of prolonged systemic administration of this cytokine on total skeletal Ca, somatic growth and joint tissue has not yet been investigated. Methods: Five groups of 14 rats each, aged 7–8 weeks, had miniosmotic pumps (Alzet 200 μl) implanted and primed to release 100, 200, 500, 1,000 and 2,000 ng/kg/24 h of human recombinant IL-1β (rIL-1β) daily for 14 days. On days 0 and 14 total skeletal mineral content (BMC) was assessed by means of X-ray absorptiometry and vertebral and tibial growth was measured by computer-assisted radiometry. On the same days, blood was drawn and analyzed for rat growth hormone (rGH), insulin-like growth factor (IGF-1), and osteocalcin. Also 24-hour urine was collected for d-pyridinoline (dpd) determinations. Hind- and forepaw diameter as a parameter of joint inflammation was assessed using a micrometric calliper. Subsequently the animals were sacrificed and one tibia dissected for measurement of trabecular volume by computerized histomorphometry. Results: BMC decreased in a dose-dependent manner reaching significance at 1,000 and 2,000 ng/kg (p < 0.03 and 0.04) in close correlation with tibial trabecular volumes (r = 0.84; p < 0.02). Normal vertebral and tibial growth was recorded at all dosages. There was no evidence of joint involvement. Blood rGH and IGF-1 remained normal as did osteocalcin, the latter reflecting lack of osteoblast activation. In contrast dpd increased in a dose-dependent manner indicating enhanced bone matrix turnover. Conclusion: It is concluded that graded infusions of supraphysiological doses of rIL-1β capable of inducing osteopenia did not affect skeletal growth in the absence of articular reaction. This is in contrast with the experience recorded in experimental arthritis in which growth retardation, in addition to osteopenia, may be caused by factors other than circulating IL-1β. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: TGF-β1, which is one of the profibrogenic cytokines, is considered essential for both the tubulointerstitial fibrosis found in chronic kidney diseases and the repair of tissue damage in acute renal injury. Iron plays an important part in inflammatory damage since it supplies cytotoxic hydroxyl radicals. The aim of the present study was to examine the direct effects of iron on TGF-β1 production and the expression of 8-hydroxy-2′-deoxyguanosine (8-OHdG), a marker of oxidative stress, by human renal proximal tubular epithelial cells (RPTEC). Methods: Using human RPTEC, TGF-β1 expression was studied by immunohistochemical staining, ELISA and RNase protection assays. 8-OHdG expression was evaluated by immunohistochemical staining. Results: Ferric iron suppressed both TGF-β1 secretion and mRNA expression, and enhanced 8-OHdG expression in RPTEC in a dose-dependent manner. Desferrioxamine, an iron chelator, eliminated the suppressive effect of ferric citrate on TGF-β1 production. Conclusions: The results suggest that iron may delay the repair of kidney injury during the acute inflammatory phase via a reduction in TGF-β1 production by RPTEC. Iron chelation may therefore be a useful strategy in the treatment of inflammatory kidney diseases. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Interleukin-6 (IL-6) is a pleiotropic cytokine produced by numerous types of immune and nonimmune cells and is involved in many pathophysiologic mechanisms in humans. Many studies suggest that IL-6 is a putative ‘sleep factor’ and its circadian secretion correlates with sleep/sleepiness. IL-6 is elevated in disorders of excessive daytime sleepiness such as narcolepsy and obstructive sleep apnea. It correlates positively with body mass index and may be a mediator of sleepiness in obesity. Also the secretion of this cytokine is stimulated by total acute or partial short-term sleep loss reflecting the increased sleepiness experienced by sleep-deprived individuals. Studies that evaluated the 24-hour secretory pattern of IL-6 in healthy young adults suggest that IL-6 is secreted in a biphasic circadian pattern with two nadirs at about 08.00 and 21.00, and two zeniths at about 19.00 and 05.00 h. In contrast, following sleep deprivation or in disorders of sleep disturbance, e.g., insomnia, IL-6 peaks during the day and, based on the level of stress system activity, i.e., cortisol secretion, contributes to either sleepiness and deep sleep (low cortisol) or feelings of tiredness and fatigue and poor sleep (high cortisol). In order to address concerns about the potential impact of differences of IL-6 levels between the beginning and the end of the 24-hour blood-drawing experiment, we proceeded with a cosinor analysis of ‘detrended’ data in young and old healthy individuals. This new analysis did not affect the biphasic circadian pattern of IL-6 secretion in young adults, while it augmented the flattened circadian pattern in old individuals in whom the difference was greater. Finally, IL-6 appears to be somnogenic in rats and exhibits a diurnal rhythm that follows the sleep/wake cycle in these animals. We conclude that IL-6 is a mediator of sleepiness and its circadian pattern reflects the homeostatic drive for sleep. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: This study was designed to determine immune and hormonal changes and their relationship with the incidence of upper respiratory tract infections (URTIs) during an extremely stressful military training (3 weeks of physical conditioning followed by a 5-day combat course with energy restriction, sleep deprivation and psychological stress). Methods: Blood samples were collected from 21 cadets (21 ± 2 years old) before training and after the combat course for analysis of leukocyte and lymphocyte subpopulations, serum cytokines [interleukin-6 (IL-6), IL-1β and IL-10], and hormones [catecholamines, cortisol, leptin, total insulin-like growth factor I (IGF-I), prolactin, dehydroepiandrosterone sulfate (DHEAS) and testosterone]. Symptoms of URTI were recorded from health logs and medical examinations during training. Results: After the combat course, total leukocyte and neutrophil counts were significantly increased while total lymphocytes were unchanged. In lymphocyte subsets, NK cells were reduced (p < 0.01), while CD4+ and CD19+ (B) cells were increased. Levels of IL-6 were increased (p < 0.01), while those of IL-1β and IL-10 were unchanged. Norepinephrine and dopamine levels were increased, while those of cortisol were reduced. Levels of leptin, testosterone, prolactin and total IGF-I were reduced, while those of DHEAS were increased. The incidence of URTI increased during the training (χ2 = 53.48, p < 0.05). After training data analysis showed a significant correlation between URTIs and NK cells (p = 0.0023). Training-induced changes in immune and hormonal parameters were correlated. Conclusions: Blood NK cell levels are related to increased respiratory infections during physical training in a multistressor environment. The training-induced decreases in immunostimulatory hormone levels may have triggered immunosuppression. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Since α-melanocyte-stimulating hormone (α-MSH) inhibits the synthesis and release of proinflammatory cytokines and stimulates the synthesis and release of anti-inflammatory cytokines, and leptin is a cytokine that has anti-inflammatory actions in the presence of lipopolysaccharide (LPS), we hypothesized that α-MSH increases leptin synthesis and release. Methods: α-MSH or 0.9% NaCl (saline) were injected intraperitoneally 15 min prior to intravenous injection of 0.5 ml of saline or LPS (0.15 mg/kg). Thereafter, repeated blood samples were withdrawn over a period of 6 h and plasma leptin concentrations determined. The rats were sacrificed at 6 h and leptin mRNA was measured in epididymal fat pads. Results: Plasma leptin concentrations of the saline-injected control group were unaltered during the 6 h, whereas in the LPS group, leptin was unaltered between 0 and 30 min and thereafter progressively increased between 30 and 360 min by 2.5-fold. α-MSH slightly increased plasma leptin concentrations by 15 min and then increased them further by 120 min, after which they declined towards baseline. The pattern of plasma leptin concentrations in the α-MSH + LPS group was similar to that of the LPS group, except that higher concentrations were observed at 120 min in the rats injected with α-MSH + LPS. LPS increased leptin mRNA by 3-fold at 6 h, whereas it was unaffected in the MSH-treated animals. On the contrary, α-MSH completely blocked the LPS-induced leptin mRNA. Conclusions: Our results suggest that α-MSH increased leptin release without altering its synthesis, but when LPS increased release and synthesis of leptin, α-MSH, although further increasing release, blocked the enhanced synthesis of leptin elicited by LPS. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective(s): The implantation process is closely linked to the fundamental question of the tolerance of the maternal immune system. The main objective of this study was to investigate whether different members of the transforming growth factor-β (TGF-β) superfamily could intervene in the first steps of embryo implantation by modulating the secretion of proimplantatory leukemia inhibitory factor (LIF) and in the tolerance of the fetal graft by regulating proinflammatory interleukin (IL)-6 secretion by human endometrial epithelium (EEC) in vitro. Methods: EEC were isolated from biopsies collected from 16 informed and consenting fertile women and were cultured for 72 h. Cytokine measurements (LIF and IL-6) were realized by ELISA. Results: TGF-β1 (from 10–12 to 10–8M), -β2, -β3 and activin A (10–10 and 10–8M) increased LIF secretion by EEC cultures. Inhibin B (10–10 and 10–8M) did not stimulate LIF production by human EEC. Contrastingly, TGF-β1 (from 10–12 to 10–8M), -β2, -β3 and activin A (10–10 and 10–8M) reduced IL-6 release by the same cells. Activin A at 10–8M also significantly reduced the stimulating effect of IL-1β (10–9M) which is known to stimulate LIF production by EEC. Only the highest concentration of inhibin B (10–8M) reduced IL-6 secretion by EEC, but did not modulate IL-1β-induced stimulation of IL-6 secretion. Conclusion(s): Besides their role in the control of the process of implantation and in the induction of embryonic mesoderm, different members of the TGF-β superfamily may also contribute in the reproductive process by enhancing endometrial proimplantatory LIF secretion and reducing proinflammatory IL-6 release by EEC. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The central nervous system can regulate the peripheral immune system. Moreover, differences between left and right hemispheres (neurochemical brain asymmetries) and behavioral lateralization (functional brain asymmetries) affect immune responses. The molecular basis of brain-immune interactions remains insufficiently understood. Cytokines regulate immune responses, possibly through activation of the hypothalamic-pituitary-adrenal (HPA) axis. HPA axis activities are related to behavioral lateralization and brain asymmetry. Given IL-6 plays a role in asymmetrical brain immunomodulation, one might expect the IL-6 distribution in brain to be asymmetrical and to depend on behavioral lateralization. In order to start to test this hypothesis, male C57BL/6J mice were selected for paw preference and assessed for IL-6 levels in right and left cortex and hippocampus by enzyme linked immunosorbent assay. The results showed asymmetrical distribution of brain IL-6 in left-pawed animals and ambidextrous animals, but not in right-pawed animals, both in cortex and hippocampus. Furthermore, we found a correlation between IL-6 hemispheric distribution and the degree of behavioral lateralization both in cortex and hippocampus. Altogether, these results suggest that brain IL-6 could be a mediator of asymmetrical immunomodulation by the central nervous system. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background/Aims: Thyroid function impairment has been sporadically described in cystic fibrosis (CF) and ascribed to iodine overload or selenite deficiency. In this study we evaluated thyroid function in CF in order to verify these data and to evaluate if the modifications were related to serum levels of markers of inflammation and growth factors that we have previously shown to be altered in CF. Methods: Seventeen young adult CF patients and 18 age-matched controls were enrolled in this study. The diagnosis of CF was confirmed by genetic analysis. None was treated with pulmonary expectorants. Serum IL-1β, IL-6, TNF-α, IGF-I, IGF-II, IGFBP-2, IGFBP-3, TSH, fT3 and fT4 were measured using standard commercial kits. Results: TSH, fT3 and fT4 serum levels were similar in CF patients and controls. Within the patient group, thyroid function did not vary in relation to C-reactive protein serum levels, respiratory function and clinical conditions (Shwachman score). No correlation was found with any growth factor or cytokine analyzed. Conclusions: At variance with the few previously published data, we did not detect any difference in thyroid function in patients with CF compared with normal healthy subjects. This could be due to the fact that no iodine overload or selenite deficiency was present in our patients. Thyroid function seemed independent of markers of inflammation and IGF-IGFBP serum levels. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objective: Our previous study indicated an association between cellular immune reactivity to common dietary proteins (DPs) and excessive proinflammatory cytokine production with endotoxin (lipopolysaccharide, LPS), a major stimulant of innate immunity in the gut mucosa, in a subset of autism spectrum disorder (ASD) children. However, it is unclear whether such abnormal LPS responses are intrinsic in these ASD children or the results of chronic gastrointestinal (GI) inflammation secondary to immune reactivity to DPs. This study further explored possible dysregulated production of proinflammatory and counter-regulatory cytokines with LPS in ASD children and its relationship to GI symptoms and the effects of dietary intervention measures. Methods: This study includes ASD children (median age 4.8 years) on the unrestricted (n = 100) or elimination (n = 77) diet appropriate with their immune reactivity. Controls include children with non-allergic food hypersensitivity (NFH; median age 2.9 years) on the unrestricted (n = 14) or elimination (n = 16) diet, and typically developing children (median age 4.5 years, n = 13). The innate immune responses were assessed by measuring production of proinflammatory (TNF-α, IL-1β, IL-6, and IL-12) and counter-regulatory (IL-1ra, IL-10, and sTNFRII) cytokines by peripheral blood mononuclear cells (PBMCs) with LPS. The results were also compared to T-cell responses with common DPs and control T-cell mitogens assessed by measuring T-cell cytokine production. Results: ASD and NFH PBMCs produced higher levels of TNF-α with LPS than controls regardless of dietary interventions. However, only in PBMCs from ASD children with positive gastrointestinal (GI(+)) symptoms, did we find a positive association between TNF-α levels produced with LPS and those with cow’s milk protein (CMP) and its major components regardless of dietary interventions. In the unrestricted diet group, GI(+) ASD PBMCs produced higher IL-12 than controls and less IL-10 than GI(–) ASD PBMCs with LPS. GI(+) ASD but not GI(–) ASD or NFH PBMCs produced less counter-regulatory cytokines with LPS in the unrestricted diet group than in the elimination diet group. There was no significant difference among the study groups with regard to cytokine production in responses to T-cell mitogens and other recall antigens. Conclusion: Our results revealed that there are findings limited to GI(+) ASD PBMCs in both the unrestricted and elimination diet groups. Thus our findings indicate intrinsic defects of innate immune responses in GI(+) ASD children but not in NFH or GI(–) ASD children, suggesting a possible link between GI and behavioral symptoms mediated by innate immune abnormalities. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Objectives: The complement system is critical to the febrile response of mice to intraperitoneally administered lipopolysaccharide (LPS). We previously identified C3 and C5 as two components potentially involved in this response. This study was designed to examine whether the complement system is also pivotal in the response of mice to intravenously or intracerebroventricularly injected LPS, to distinguish between C3 and C5 and their cognate derivatives as the essential mediator(s), and to determine whether the failure of complement-deficient mice to develop a fever could be due to their possible inability to secrete pyrogenic cytokines. Methods: Wild-type (WT; C57BL/6J) mice, hypocomplemented or not by intravenously injected cobra venom factor (10 U/mouse), and C3-, CR3- and C5-sufficient and -deficient mice were intravenously challenged with LPS (0.25 μg/mouse); WT and C3–/– mice pretreated with a C5a receptor antagonist (C5aRa) were similarly challenged. In addition, the serum levels of interleukin (IL)-1β, tumor necrosis factor (TNF)-α and IL-6 were compared in LPS-treated C5+/+ and C5–/– mice. Results: LPS induced a 1°C rise in core temperature in all the mice, except C5–/– mice and those pretreated with C5aRa. C5+/+ and C5–/– mice challenged intracerebroventricularly with LPS exhibited identical febrile responses. LPS induced similar increases in the serum levels of IL-1β, TNFα and IL-6 in C5+/+ and C5–/– mice. Conclusions: C5a is crucial for the development of febrile responses to LPS in mice; its site of action is peripheral, not central. The possibility that an inability to produce cytokines could account for the failure of C5–/– mice to develop a fever is not supported. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

We have reported that Vasogen’s immune modulation therapy (IMT), a procedure involving intramuscular administration of autologous/syngeneic blood, which has been exposed ex vivo to increased temperature, UVC light and oxidation, prevents several LPS-induced inflammatory changes in the hippocampus. Here, we investigated neuroprotective effects of IMT in cortical tissue, and report that the treatment acts as an anti-inflammatory and antioxidative agent, reducing the concentration of TNFα and the accumulation of reactive oxygen species. The data couple these changes with an increase in the concentration of the anti-inflammatory cytokine IL-10, and a decrease in activation of the stress-activated protein kinase, c-jun N-terminal kinase. Consistent with these putative protective effects of IMT, we report that the LPS-induced increase in TUNEL staining, which is indicative of cell death, is prevented by IMT. Copyright © 2005 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Anergy, tolerance and active suppression may not be independent events, but rather involve similar mechanisms and cell types in immune regulation. Induction of allergen-specific regulatory/suppressor T cells (TReg) seems essential for the maintenance of a healthy immune response to allergens. Allergen-specific immunotherapy can induce specific TReg cells that abolish allergen-induced proliferation of T helper 1 (Th1) and Th2 cells, as well as their cytokine production. TReg cells utilize multiple suppressive mechanisms, interleukin-10 (IL-10) and transforming growth factor-β (TGF-β) as secreted cytokines and CTLA-4, PD-1, mTGF-β, mIL-10, TGF-βR and IL-10R as surface molecules. An important aspect of TReg cells is the regulation of antibody isotypes and suppression of proinflammatory cells. IL-10 and TGF-β secreted by TReg cells skew production of IgE towards the noninflammatory isotypes, IgG4 and IgA, respectively. Furthermore, TReg cells may directly or indirectly suppress effector cells of allergic inflammation such as basophils and eosinophils. In conclusion, induction of antigen-specific TReg cells may redirect an inappropriate immune response against allergen or autoantigens with the help of a broad range of suppressor mechanisms. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Among human cancers, melanoma is characterized by an almost unique predisposition to regress in response to immune therapy. Recent clinical studies suggest that the frequency of this favorable event is enhanced by combining T-cell-directed active specific immunization with the systemic administration of interleukin (IL)-2. While waiting for additional clinical experience to confirm this observation, we embraced the working hypothesis that this combination provides superior response rates than either treatment alone. In particular, we have focused our interest on the paradoxical observation that active specific immunization consistently induces circulating CD8+ T cells capable of recognizing in ex vivo assays tumor cells, but cannot induce tumor regression alone. In these settings, it appears that combining the systemic administration of IL-2 is almost an absolute requirement for the induction of clinical responses. Here, we will expand on previous speculations on the postulated mechanism(s) of action of systemic IL-2 administration and, based on original data recently derived through high-throughput transcriptional and post-translational analysis, we will suggest an explanation for the eclectic effects of IL-2 administration in the context of active specific immunization. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The development of new blood vessels, i.e. angiogenesis, is a rate-limiting step in the development of tumors since tumor growth is generally limited to 1–2 mm3 in the absence of a blood supply. Thus, the inhibition of tumor growth by attacking the tumor’s vascular supply offers a primary target for antiangiogenic intervention by DNA-based vaccines. Here, we describe two novel orally delivered DNA vaccines which suppress tumor angiogenesis and induce a robust cell-mediated immune response that provides for long-lived protection against melanoma, colon, breast and non-small-cell lung carcinoma in mouse model systems. These vaccines, which are delivered by attenuated Salmonella typhimurium to secondary lymphoid organs, are directed against such targets as vascular endothelial growth factor receptor 2 (FLK-1) and transcription factor Fos-related antigen 1 (Fra-1). Both vaccines break peripheral T cell tolerance against these self-antigens and induce a robust T cell-mediated immune response leading to suppression of tumor angiogenesis and resulting in effective suppression of tumor growth and metastases. Such research efforts may open up new possibilities for the rational design of future DNA vaccines effective for the prevention and treatment of cancer. Copyright © 2004 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Despite the progress that has been made in intensive care medicine, multiple organ failure is still associated with high mortality. Apart from the prevention of infectious complications, numerous efforts are being made to improve the treatment of sepsis through adequate antibiotic therapy, the development of new respirator therapies, better control of the hemodynamic situation, and adequate renal replacement therapy. Some authors advocate continuous renal replacement therapy not only for acute renal failure but also for the elimination of inflammatory molecules such as cytokines. Continuous renal replacement therapy improves the cardiovascular hemodynamics in patients with multiple organ failure. Therapeutic options such as volume control, clearance of uremic toxins, correction of acid base disturbances and temperature control are improved. Suitable renal replacement therapy improves not only cardiovascular hemodynamics but also patient survival. In current practice, continuous renal replacement therapy is not used to eliminate mediators such as cytokines. In patients with multiple organ failure and compromised cardiovascular hemodynamics, renal replacement therapy should be carried out as early as possible. In the following review, experimental and clinical findings concerning mediator elimination by continuous and intermittent renal replacement therapy are summarized.Copyright © 2003 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Background: Preclinical stages of type 1 diabetes are characterized by infiltrating T cells and by the peri- and intra-islet accumulation of pro-inflammatory mediators, such as IFNγ. Methods/Results: Using quantitative PCR we demonstrated that mRNA specific for the IFNγ-inducing cytokine IL-18 is upregulated in NIT-1 beta cells and intact mouse islets upon exposure to IL-1β, IFNγ and TNFα. The biological activity of IL-18 was blocked using caspase inhibitors and anti-IL-18 antibodies. Increased IL-18 expression was also detected in islets during advanced stages of insulitis and correlated with elevated transcripts for IFNγ and for the IL-18 receptor. Conclusion: Thus, beta cells produce bioactive IL-18 in the course of insulitis and actively contribute to the exacerbation of inflammation leading to their own demise.Copyright © 2002 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]