Intraventricular Neurocysticercosis: Comparative Analysis of Different Localizations. Clinical Course and Treatment. A Systematic Review.

Background Neurocysticercosis is significant due to its high prevalence and considerable morbidity and mortality. The intraventricular form of NCC is less common than parenchymal, may have a rapidly progressive course and it requires a corresponding therapeutic response. Despite the extensive literature dealing with NCC and intraventricular cystic lesions, no systematic reviews have addressed similar work related to the clinical course and treatment of the infestation. Our main objective was to analyze the clinical type of the disease and the management for each ventricle separately on the basis of case reports or series of patients with individual data on the course of the disease and its treatment. As a control group, we used data on signs&symptoms and treatment of patients from published series on intraventricular neurocysticercosis. Method We performed a search in the Medline database. Google Scholar was also randomly searched. We extracted the following data from the eligible case/series: age and gender, symptoms, clinical signs, diagnostic examinations and findings, localization, treatment, follow-up period, outcome, and publication year. All data are presented in the form of absolute and relative numbers. The frequency of signs and symptoms, treatment and outcomes of the observed groups were checked by the Chi-square test and Fisher's test. The hypothesis was tested with p <0.05 as statistical significance. Results We selected 160 cases of intraventricular neurocysticercosis (IVNCC) and divided them according to their localization into five categories. Hydrocephalus was recognized in 134 cases (83.4%). Patients with isolated IVNCCare are younger (P=.0264) and have a higher percentage of vesicular cysts (p <.00001). In mixed IVNCC, degenerative and multiple confluent cysts predominate (p = 0.00068). Individuals carrying fourth + third ventricular cysts (potentially obstructive form) are younger than individuals with lateral ventricles (potentially less obstructive forme) (p = .0083). The majority of patients had individual symptoms for a longer period before the acute onset of the disease (p <.00001). The predominant clinical manifestation is headache (88.7%); the proportion within the groups ranged from 100% to 75% without statistical significance (p.074214). The same was true for patients with symptoms of vomiting or nausea, who had a lower and roughly balanced percentage of 67.7% to 44.4% (p.34702). Altered level of consciousness (ranging from 21% to 60%) and focal neurological deficit (from 51.2% to 15%) are the only clinical category with statistical significance (p <0.001 and p.023948 ). Other signs and symptoms were less frequent and statistically irrelevant. Surgical resection of the parasite was the predominant type of treatment, varying from 55.5% to 87.5% (p- .02395); endoscopy (48.2%) and craniotomy (24.4%), each individually, showed statistical significance (.00001 and .000073, respectively). The difference was also relevant among patients who had CSF diversion performance with/without medical treatment (p-.002312. Postoperatively, 31.8% of patients received anthelmintics with/without anti-inflammatory or other drugs. Endoscopy, open surgery, and postoperative antiparasitic therapy showed statistical differences (p < 0.001). Favorable outcomes or regression of symptoms were recorded in 83.7%, mortality 7.5%. In the case series, the clinical signs&symptoms were as follows: headache-64%, nausea and vomiting 48.4%, focal neurological deficit 33.6% and altered level of consciousness 25%. Open surgery was the predominant form of intervention (craniotomy (57.6% or endoscopy 31.8%); with statistical significance between them (p< .00001). Conclusion. Ventricular neurocysticercosis is an alarming clinical condition. Hydrocephalus is the dominant diagnostic sign. Isolated IVNCC patients were recognized at a younger age than Mix.IVNCC individuals; poeple with cysts in the fourth and third ventricles (as a potentially more occlusive type of disease), presented their symptoms at a younger age than individuals with LVNCC. The majority of patients had long-term signs and symptoms before the acute onset of the disease. Headache, nausea& vomiting are the most common symptoms of infestation accompanied by altered sensorium and focal neurological deficits. Surgery is the best treatment option. A sudden increase in ICP due to cerebrospinal fluid obstruction with a successive cerebral hernia is the leading cause of fatal outcomes.

Behavioral and Dietary Habits That Could Influence Both COVID-19 and Non-Communicable Civilization Disease Prevention-What Have We Learned Up to Now?

The massive expansion of the new coronavirus SARS-CoV-2 has urged countries to introduce lockdowns and set restrictive actions worldwide. The focus of the studies was to determine how COVID-19 induces damage to the lungs in order to find an alternative or adjuvant therapy that could lead to preventing COVID-19 or at least ameliorating it. This paper aims to survey the literature and provide new insights into behavioral and dietary habits that could influence the prevention of COVID-19. Maintaining an adequate mental health status, sleep, and taking moderate exercise are often disrupted in the conditions of lockdown and are followed by weakened immunity. Mediterranean and vegetarian diets are superior to other eating patterns in terms of immunity boosting and fighting COVID-19. Our study showed how adequate hydration, green tea intake, and supplementation with vitamins D, C, and E can increase our chances of avoiding the infection and even help us sleep better. Another focus of the research was on determining what level of hygiene really increases one's chances of not contracting SARS-CoV-2, but this seems a little counter-intuitive at first. Since an immunocompromised state is a familiar predisposing factor for all contagious diseases, maintaining healthy behavioral and dietary habits could be a crucial step in boosting immunity and preventing COVID-19.

Immunomodulatory Effects of Extract of Lingzhi or Reishi Medicinal Mushroom Ganoderma lucidum (Agaricomycetes) Basidiocarps Cultivated on Alternative Substrate.

Ganoderma lucidum is a medicinal mushroom exhibiting numerous health benefits primarily based on strong immunostimulatory effects. The study aimed to investigate if there were differences in effects of extracts of commercially (GC) and alternatively (wheat straw) (GA) cultivated G. lucidum basidiocarps on properties of peritoneal macrophages (PM) and monocyte-derived dendritic cells (MoDCs). Differences in immunomodulatory effects of GC/GA extracts were studied. The viability of treated PMs, their adhesive and phagocytic capability, and their capacity to produce reactive oxygen species (ROS) and NO were tested. Immature MoDCs generated from human monocytes were treated with poly I:C (10.0 µg/ml) and loxoribine (34.0 µg/ml), a selective TLR3 and TLR7 agonists, respectively, and with/without GC/GA extract (100.0 µg/ml). The effect of each combination on phenotypic properties, cytokines production by MoDCs, and their proliferation and Th polarizing capacity was studied. GA extract stimulated the metabolic and phagocytic activity of PMs, their adhesion capability, and ability to produce ROS and NO more strongly compared to GC. Both tested extracts significantly increased allostimulatory and Th1 polarization capacity of simultaneous TLR3 and TLR7-activated MoDCs, but GA extract was more effective. The extract of alternatively cultivated G. lucidum basidiocarps increased production of ROS and NO by TLR4 stimulated PMs and upregulated production of certain cytokines as well as allostimulatory and Th1 polarization capacity of MoDCs. GA extract could be a potent immunostimulatory agent for activation of MoDCs with the simultaneous engagement of TLRs, which seems to be a promising strategy for the preparation of DC-based anti-tumor vaccines.

Ex vivo study of IL-6 expression and function in immune cell subsets from human periapical lesions.

AIM: Even though IL-6 is a key inflammatory cytokine in periapical lesions (PLs), its function in stable periapical disease is unknown. Therefore, the aim of this study was to investigate the following: first, the ex vivo production of IL-6 by clinically different PLs; next, subsets of immune cells expressing IL-6 in PLs according to their inflammatory status and finally, modulatory effect of IL-6 on T-cell cytokine production in cell cultures. METHODOLOGY: Inflammatory cells were isolated from a total of 95 human PLs. Detection of IL-6+ cells within the myeloid and lymphoid populations was performed by multicolour flow cytometry. ELISA and FlowCytomix Microbeads Assay were used to measure cytokine levels in culture supernatants. To study the role of IL-6 in PLs, mononuclear cells (MNC) from symptomatic (Sy) or asymptomatic (Asy) PLs were treated with IL-6 or Tocilizumab, an IL-6R blocking antibody. The differences between groups were tested by unpaired t-test, Mann-Whitney or Friedman tests. RESULTS: The levels of IL-6 in PL MNC culture supernatants were significantly higher compared with total PL cells and PL granulocytes (p < .001). MNC from Sy PLs produced significantly higher levels of IL-6 than MNC from Asy PLs (p < .001). Flow cytometry analysis showed that NKT cells, CD8+ T cells and M2 macrophages (MØ), were dominant IL-6+ cells, in contrast to CD4+ T cells. However, CD8+ and CD4+ T cells contributed the most to IL-6 production. IL-6hi producing MNC cultures had higher levels of Th1 (IFN-γ), Th17 (IL-17A), Tfh (IL-21) and RANKL, whereas Th2 (IL-4) and Tregs cytokines (IL-10, TGF-ß) were lower compared with IL-6low -producing cultures. Exogenous IL-6 stimulated 17A, IL-21 and RANKL, independently of PL activation status, but decreased IFN-γ, IL-4 and IL-33 levels in IL-6hi -producing cultures. Tocilizumab increased IL-10 and TGF-ß in IL-6low -producing cultures. All differences were p < .05. CONCLUSIONS: Most immune cells from Sy PLs expressed higher levels of IL-6 compared with Asy PLs, which correlated with IL-6 production in culture. Analysis of cytokines suggested a dominant pro-inflammatory T-cell response and osteodestructive function of IL-6 in PLs judging by Th17/Tfh cell activation, Tregs inhibition and increased RANKL/OPG ratio. Excessive IL-6 production decreased Th1/Th2 responses.

The role of vitamin A and vitamin D in modulation of the immune response with a focus on innate lymphoid cells.

The immune system with its numerous and complex interactions helps to protect the host from pathogenic microorganisms, and enables cleaning of damaged tissues. It is also associated with constant "monitoring" of the appearance of malignant cells and their elimination that can occur in the human body. Such a role depends on many factors including adequate intake of nutrients, including vitamins. The effect of vitamin supplementation on the modulation of the immune response has always been the focus of numerous studies. Vitamins A and D have been shown to have the greatest immune-modulatory effect. In this review, we discuss and consider the possible roles of vitamins A and D on the immune response through innate and adaptive immune cells, with special focus on the cell population recently characterized as innate lymphoid cells. Recent literature data indicate that vitamin A and its metabolites modulate the balance between Th1 and Th2 immunity. In addition, vitamin D expresses protective effects on the innate immune system and inhibitory effects on adaptive immunity.

Immunomodulatory effects of galectin-1 in patients with chronic lymphocytic leukemia.

Galectin-1 (Gal-1) has been implicated in the progression of chronic lymphocytic leukemia (CLL) but also the development of immunodeficiency, which commonly accompany this malignancy. In this in vitro study, we investigated the effects of Gal-1 inhibition in the sera of immunocompromised CLL patients on immunomodulating properties of dendritic cells (DCs). DCs derived from peripheral blood mononuclear cells were treated with a healthy serum, CLL serum as well as the combination of CLL serum and Gal-1 inhibitor (OTX008). Following the treatment, the expression levels of DC maturation markers (CD80, CD83, CD86 and IDO-1) were determined as well as their cytokine profile and the ability to polarize the immune response in co-cultures with CD4+ T cells. After treatment with CLL serum, an increase in interleukin (IL)-10 production was observed in both DC cultures and co-cultures with CD4+ T cells. OTX008 caused a reduction in IL-10 production as well as IL-2, but no significant alteration in the expression of DC maturation markers or T regulatory cell (Treg) frequency was observed. The results of our study suggest that Gal-1 from CLL serum give rise to a specific IL-10+ CD4+ T cell phenotype, other than Treg, that could mediate immunodeficiency development in CLL patients.

Effects of galectin-1 on immunomodulatory properties of human monocyte-derived dendritic cells.

Our study aimed to evaluate the effects of Gal-1 in dose depending manner on maturation and immunomodulatory properties of monocyte-derived (Mo) DCs in-vitro. The effects were analyzed by monitoring their phenotypic characteristics, cytokine profile, and the ability to direct the immune response in the co-culture with allogeneic CD4+T cells. Gal-1 reduced the expression of CD80 and CD86 molecules on MoDCs compared to untreated MoDCs. Gal-1 at concentrations of 1 and 6 µg/mL significantly reduced IL-12 production, while the concentration of 3 µg/mL led to its significant increase. Gal-1 in all concentrations induced a significant increase in the production of IL-10. Treatment of MoDCs with 3 and 6 µg/mL of Gal-1 stimulated the production of IL-2 and IFN-γ in the co-culture with CD4+T lymphocytes. This study demonstrated a dual immunomodulatory effect of Gal-1 on MoDCs in terms of immune stimulation and immune suppression, depending on the applied concentration.

Function of innate lymphoid cells in the immune-related disorders.

Innate lymphoid cells (ILCs) are a recently described group of innate immune cells that mirror the characteristics of CD4+ T cell subsets. Based on their transcriptional factor and cytokine profile, ILCs family is divided into main subgroups-ILC1s, ILC2s, and ILC3s. Recently, one new subpopulation of ILCs with immunosuppressive characteristics has been described and named as regulatory ILCs. Various roles of ILCs have been confirmed including the role during the response to microbial signals, the role in inflammation and process of tissue repair. Function of ILCs is mediated through the cytokines production and direct cell-to-cell contact. This article summarizes in detail, the relationship between the ILCs and various immune-related disorders.

Effects of silica-rich water on systemic and peritoneal inflammation in rats exposed to chronic low-level (900-MHz) microwave radiation.

Immunomodulating effect of silica-rich water represents a novel field for research, especially regarding its features toward environmental pollutants. The aim of our study was to evaluate the effects of silica-rich water intake on systemic and peritoneal inflammation in rats that were chronically exposed to the low-level microwave (MW) radiation from mobile phones. Wistar Albino rats were exposed to 900 MHz MW radiation for 3 months. The four-treatment model involved rats with standard water (SW) or experimental silica-rich water intake (EW). Peritoneal macrophages (PMs) were harvested using peritoneal lavage and divided into non-stimulated and lipopolysaccharide (LPS) stimulated subgroups. The MW-exposed rats with silica-rich water (MW+EW) had lower serum tumor necrosis factor α (TNF-α) and interleukin 2 (IL-2) levels, but higher IL-10 levels, than MW+SW rats (p < 0.05). The higher TNF-α production by non-stimulated MW exposed PMs was ameliorated by the silica-rich water (p < 0.01). The MW exposition suppressed LPS potential for TNF-α synthesis in both water type groups, with greater suppression in animals that took standard water. Our results show the modulating effect of silica-rich water toward MW-induced systemic and peritoneal inflammation, which reflects the water ability to shape monocyte plasticity, thereby altering the balance between their proinflammatory and anti-inflammatory properties.

Effect of silicon-rich water intake on the systemic and peritoneal inflammation of rats with chronic low levels of aluminum ingestion.

BACKGROUND AND OBJECTIVES: Study evaluated effect of silicon-rich water intake on systemic inflammation and functional characteristics of peritoneal macrophages (PMs) of rats that were chronically exposed to dietary aluminum. METHODS: One month-old female Wistar Albino rats were administered aluminum chloride dissolved in distilled water (1.6mg/kg body weight in 0.5mL) by gavage for 90days. The rats were then given standard (6mg/L) or silicon-rich water (19mg/L silicon) (n=7/group). Control rats underwent sham gavage and received standard or silicon-rich water (n=7/group). Blood was assessed for cytokine levels. Unstimulated and lipopolysaccharide (LPS)-stimulated PMs were assessed in terms of phagocytic activity and cytokine secretion in vitro. RESULTS: Chronic exposition to dietary aluminum and silicon-rich drinking water did not change serum TNF-α levels. Aluminum increased serum IL-2 and this was reversed by silicon-rich water. The aluminum-exposed rats had higher serum sICAM-1 than sham-gavaged, unrelated to type of water. LPS-stimulated PMs from aluminum-intoxicated animals exhibited low phagocytic activity and release of TNF-α, this was significantly improved by silicon-rich water intake. In the presence of silicon-rich water, LPS-stimulated and unstimulated PMs from aluminum-exposed rats produced significantly more IL-10. CONCLUSIONS: Chronic ingestion of aluminum, increases systemic and peritoneal inflammation and PM dysfunction. The presence of high levels of the natural aluminum antagonist silicon in the drinking water restored IL-10 and TNF-α PM secretion, preventing prolonged inflammation. Thus, silicon intake can decrease the immunotoxicity of aluminum.

Tumor necrosis factor-α promotes survival and phenotypic maturation of poly(I:C)-treated dendritic cells but impairs their Th1 and Th17 polarizing capability.

BACKGROUND AIMS: Toll-like receptor (TLR)-3 synthetic agonist polyinosinic-polycytidylic acid (poly(I:C)) is a promising agent for dendritic cell (DC)-based anti-tumor vaccines because of its ability to induce a strong maturation of DCs, but such an effect is followed by stimulation of DC apoptosis. Tumor necrosis factor (TNF)-α may promote the survival of poly(I:C)-stimulated DCs, but it is not known in detail how this combination affects the maturation and polarization capacity of monocyte-derived (Mo)DCs. METHODS: Immature MoDCs, generated from human monocytes, were treated with different concentrations of poly(I:C) combined with TNF-α, and the effect on survival, phenotype, production of cytokines, allostimulatory and Th polarization capacity was assessed after 24 and 48 h. RESULTS: We showed that TNF-α inhibited the dose-dependent pro-apoptotic effect of poly(I:C). However, TNF-α also decreased poly(I:C)-induced production of interleukin (IL)-12 and IL-23 by MoDCs, which correlated with their diminished capacity to stimulate cellular proliferation, interferon-γ and IL-17 production by allogeneic CD4(+)T cells in co-culture. Such an effect was more pronounced after 24 h and could not be restored by CD40 ligation. In the presence of CD40L, TNF-α even stimulated IL-10 production and immunoglobulin-like transcript 3 expression by poly(I:C)-matured DCs, which correlated with their increased capacity to induce IL-10 production by CD4(+)T cells. CONCLUSION: Even though TNF-α could promote the survival of poly(I:C)-matured MoDCs, it also suppresses key anti-tumor functions of these cells, which could have important implications when considering this, already suggested, protocol for the DC-based anti-tumor therapy.

Dose-dependent response of dendritic cells to 7-thia-8-oxo-guanosine and its modulation by polyinosinic:polycytidylic acid.

Targeting the endosomal Toll-like receptors (TLRs) by specific agonists seems to be a promising tool for stimulation of the immunogenicity of dendritic cells (DCs). Since the functional outcome upon the engagement of TLRs may be different, the aim of our study was to examine if and how different concentrations of 7-thia-8-oxo-guanosine (7-TOG), a selective TLR7 agonist, influence differentiation, maturation and functions of human monocyte-derived DCs (MoDCs) and if its effects on MoDCs could be modulated by co-ligation of TLR3. Immature MoDCs were treated with different concentrations of 7-TOG (25, 100 and 250 µmol/L) alone, or together with polyinosinic:polycytidylic acid, Poly (I:C) (10 ng/mL), a selective TLR3 agonist, for an additional 48 h. We showed that the highest concentration of 7-TOG stimulated the differentiation, maturation and allostimulatory capability of MoDCs. These changes were accompanied by an increased production of interleukin 12 (IL-12) and induction of T helper (Th)1 and Th17 immune responses. Both Th responses were significantly augmented by additional stimulation of MoDCs with Poly (I:C). The treatment of MoDCs with the intermediate concentration of 7-TOG resulted in the up-regulation of co-stimulatory molecule (CD86) and increased production of IL-1ß and IL-6 by MoDCs, followed by the stimulation of the Th17 immune response. The lowest concentration of 7-TOG down-regulated the expression of CD40 on MoDCs and potentiated the Th2 immune response. The Th2 response was not significantly modulated by additional treatment of MoDCs with Poly (I:C), but this combination of TLR3/TLR7 agonists also stimulated both Th1 and Th17 responses. In conclusion, our results show that 7-TOG influences the phenotype and functions of MoDCs in a dose-dependent manner and suggests that fine-tuned signaling through TLR7 may be modified by the engagement of TLR3, resulting in a different outcome of immune response.

The response of human dendritic cells to co-ligation of pattern-recognition receptors.

Dendritic cells (DCs) are key antigen-presenting cells that express a wide variety of pattern-recognition receptors (PRRs). Triggering of a single PRR, especially Toll-like receptors (TLRs) and C-type lectins, induces maturation of DCs, but cooperativity between multiple PRRs is needed in order to achieve an effective immune response. In this review, we summarize the published data related to the effect of individual and joint PRR agonists on DCs and Langerhans-like cells derived from monocytes (MoDCs and MoLCs, respectively). Our results demonstrate that MoDCs co-stimulated with TLR3/TLR7 and TLR3/Dectin-1 ligands induced superior T helper (Th)1 and Th17 immune responses, compared to effects of single agonists. The opposite outcome was observed after co-ligation of TLR3 and Langerin on MoLCs. These findings may be relevant to improve strategy for tumor immunotherapy.

Signaling through Toll-like receptor 3 and Dectin-1 potentiates the capability of human monocyte-derived dendritic cells to promote T-helper 1 and T-helper 17 immune responses.

BACKGROUND AIMS: Recent studies have shown that the ligation of Toll-like receptor 3 (TLR3) or Dectin-1 on human monocyte-derived dendritic cells (MoDC) elicits their maturation, but with a different outcome on immunomodulation. Therefore the aim of this work was to study the response of MoDC to the combined effect of polyinosinic:polycytydilic acid [Poly (I:C)] and curdlan, selective TLR3 and Dectin-1 agonists, respectively. METHODS: Immature MoDC, generated from human monocytes, were treated with Poly (I:C), curdlan or their combination for 2 days. Phenotypic characteristics of MoDC were determined by flow cytometry, and cytokine production was measured by enzyme-linked immunosorbent assay (ELISA) and FlowCytomix, while the stimulatory capability of MoDC was tested using a mixed leukocyte reaction assay. RESULTS: The combination of Poly (I:C) and curdlan induced phenotypic maturation of MoDC with the capability to stimulate an alloreactive response. Such treated MoDC up-regulated the production of interleukin (IL)-12, IL-23 and IL-10, compared with the effect of Poly (I:C) alone. Curdlan-treated MoDC stimulated the production of IL-17 by alloreactive CD4 (+) T cells more strongly than Poly (I:C)-treated MoDC. The opposite effect was observed for interferon(IFN)-γ production. When combined, these agonists primed MoDC to increase further the production of IFN-γ by CD4 (+) T cells in co-culture, especially those of naive (CD45RA (+)) phenotype, and IL-17 by memory (CD45RO (+)) CD4 (+) T cells. CONCLUSIONS: Ligation of TLR3 and Dectin-1 receptor up-regulates T-helper (Th) 1 and Th17 immune responses compared with single agonists. These findings may have therapeutic implications for the use of MoDC in immunotherapy.

The influence of CD40 ligation and interferon-gamma on functional properties of human monocyte-derived dendritic cells activated with polyinosinic-polycytidylic acid.

BACKGROUND/AIM: Ligation of a Toll-like receptor (TLR) by specific TLR agonists is a powerful tool for maturation induction of monocyte-derived dendritic cells (MoDCs). Studies so far have shown that the treatment of dendritic cells (DCs) with a TLR3 ligand, polyinosinic-polycytidylicacid [Poly(I:C)], may be an appropriate activation agent for obtaining mature MoDCs, competent to prime effective immune responses. However, little is known about how subsequent interaction of MoDCs with T cell-derived stimuli, such as CD40 or interferon-gamma (IFN-gamma), modulates MoDC functions. Therefore, this problem was the main objective of this study. METHODS: Immature MoDCs were prepared by cultivation of monocytes from peripheral blood mononuclear cells with granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4 for 5 days. After that, maturation was induced by the treatment of these cells with Poly(I:C) for 2 days. At day 6, immature MoDCs and Poly(I:C)-activated MoDCs were incubated either with CD40 ligand (L)-transfected J558 cells or IFN-gamma for additional 24 hours. Cytokine production was measured by ELISA and FlowCytomix Human T helper Th1/Th2 11plex. Allostimulatory capability of MoDCs was tested using an allogeneic mixed leukocyte reaction (MLR) assay. RESULTS: Immature MoDCs showed a moderate potential for stimulation of proliferation of CD4+ T cells, which was enhanced by the treatment with Poly(I:C). Ligation of CD40 or treatment with IFN-gamma of immature or Poly(I:C)-treated MoDCs significantly up-regulated their allostimulatory activity. MoDCs matured in the presence of Poly(I:C) up-regulated the production of IL-12 and IL-10, which was followed by increased levels of IFN-gamma and decreased levels of IL-5 in co-cultures with allogeneic CD4+ T cells. Ligation of CD40 on immature MoDCs upregulated the production of IL-12 and IL-23 which was accompanied by increased secretion of IFN-gamma in co-culture. Stimulation of CD40 on Poly(I:C)-treated MoDCs significantly enhanced the production of IL-12, IL-23 and IL-10. However, such treated MoDCs decreased the production of IFN-gamma and IL-10 and up-regulated the secretion of IL-17. Immature MoDCs treated with IFN-gamma up-regulated IL-12, but lowered the production of IL-5 and IL-17 by CD4+ T cells. Treatment of Poly(I:C)-activated MoDCs with IFN-gamma down-regulated the production of IL-12 and up-regulated IL-10 by these cells and increased/decreased the levels of IL-10/ IFN-gamma, respectively, in co-culture with CD4+ T cells. CONCLUSION: Treatment with Poly(I:C) or ligation of CD40 on immature MoDCs induces maturation of these cells into a phenotype that supports Th1 response. Activation of CD40 on Poly(I:C)-treated MoDCs shifts the immune response towards Th17. Treatment of immature MoDCs with IFN-gamma down-regulated Th2 and Th17 responses. However, addition of IFN-gamma to Poly(I:C)-activated MoDCs down-regulated Th1 response and promote T regulatory mechanisms. Each of these results may have functional and therapeutic implications.

Differences in T-helper polarizing capability between human monocyte-derived dendritic cells and monocyte-derived Langerhans'-like cells.

Langerhans' cells (LCs) represent a specific subset of dendritic cells (DCs) which are important for detecting and processing pathogens that penetrate the skin and epithelial barriers. The aim of our study was to explain what makes their in vitro counterparts - monocyte-derived Langerhans'-like cells (MoLCs) - unique compared with monocyte-derived dendritic cells (MoDCs). Immature MoDCs were generated by incubating peripheral blood monocytes with granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-4. The addition of transforming growth factor-ß (TGF-ß) to this cytokine cocktail resulted in the generation of MoLCs. MoLCs showed a lower expression of CD83, CD86, HLA-DR and CCR7 compared with MoDCs, regardless of their maturational status. Both immature and mature MoLCs secreted higher quantities of IL-23 compared with MoDCs and this finding correlated with a higher secretion of IL-17 in co-culture of MoLCs with allogeneic CD4(+) T cells. Mature MoLCs, which produced higher levels of IL-12 and lower levels of IL-10 compared with mature MoDCs, were more potent at inducing interferon-γ (IFN-γ) production by CD4(+) T cells in the co-culture system. In conclusion, the finding that mature MoLCs stimulate stronger T-helper 1 and T-helper 17 immune responses than mature MoDCs, makes them better candidates for use in the preparation of anti-tumour DC vaccines.

Loxoribine, a selective Toll-like receptor 7 agonist, induces maturation of human monocyte-derived dendritic cells and stimulates their Th-1- and Th-17-polarizing capability.

Recently, a guanosine analog, 7-allyl-7,8-dihydro-8-oxo-guanosine (loxoribine), has been identified as a selective Toll-like receptor (TLR)7 agonist. Bearing in mind the controversy regarding the expression of TLR7 by human myeloid dendritic cells (DCs) and its significance for functions of these cells, the goal of this study was to investigate the effect of loxoribine on differentiation, maturation and functions of human monocyte-derived (Mo)DCs. Immature MoDCs were obtained by cultivation of monocytes for 6 days with recombinant granulocyte macrophage-colony stimulating factor (GM-CSF) and interleukin (IL)-4. These cells were stimulated with loxoribine (250 µM) for an additional 48 h. Phenotypic properties of MoDCs were determined by flow cytometry, cytokine production was assayed by ELISA, whereas their allostimulatory capability was tested using a mixed leukocyte reaction. We showed that loxoribine up-regulated the expression of TLR7, CD40, CD54, CD80, CD83 and CCR7 and stimulated the production of IL-12, IL-23, IL-27 and IL-10 by MoDCs, whereas the level of interferon (IFN)-ß was not modulated. Allogeneic CD4(+)T cells in co-culture with loxoribine-treated MoDCs proliferated more strongly, at lower DC/CD4(+)T-cell ratio (1:80), and secreted significantly higher levels of IL-17 and IFN-γ compared to the cultures with control MoDCs. The stimulatory effect of loxoribine on T helper (Th)1 polarization capability of MoDCs was further potentiated by ligation of CD40. In conclusion, our results show that loxoribine stimulated differentiation, maturation, allostimulatory as well as Th1 and Th17 polarization capability of human MoDCs and suggests that these effects might be associated with up-regulation of TLR7 expression, but not increased IFN-ß production.

Production of proinflammatory and immunoregulatory cytokines by inflammatory cells from periapical lesions in culture.

BACKGROUND: The role of cytokines in pathogenesis of periapical lesions is not well understood. The aim of this study was to study the correlation between proinflammatory and immunoregulatory cytokines in periapical lesions and their relationship with cellular composition and clinical presentation. METHODS: Inflammatory cells were isolated from 67 human periapical lesions and cultivated for 24 h. The levels of proinflammatory cytokines: interleukin-1 beta (IL-1beta), IL-6, IL-8 and tumour necrosis factor alpha (TNF-alpha) and immunoregulatory cytokines: transforming growth factor-beta (TGF-beta) and IL-10 were determined in culture supernatants using a fluorescent bead immunoassay or ELISA. The phenotype of cells was analysed by immunocytochemistry. RESULTS: Inflammatory cells from symptomatic lesions which contained higher proportion of granulocytes, secreted higher levels of IL-1, IL-6 and IL-8 compared with asymptomatic lesions. Large-size lesions contained lower percentages of mononuclear phagocytes, higher percentages of CD8(+) T cells and produced higher levels of TNF-alpha, IL-6 and IL-10 compared with small-size lesions. There were negative correlations between the concentrations of TGF-beta and proinflammatory cytokines. TGF-beta, added to cultures, downregulated the levels of proinflammatory cytokines more strongly than IL-10, independently of clinical presentation of the lesions. By contrast, exogenous IL-10 was mainly immunosuppressive in cultures of asymptomatic lesions. CONCLUSION: Symptomatic lesions are characterized by higher production of proinflammatory cytokines. Immunoregulatory cytokines are more important for suppression of inflammation in asymptomatic lesions and in this context the effect of TGF-beta is more potent and different from IL-10.