CD11c depletion severely disrupts Th2 induction and development in vivo

Although dendritic cells (DCs) are adept initiators of CD4+ T cell responses, their fundamental importance in this regard in Th2 settings remains to be demonstrated. We have used CD11c–diphtheria toxin (DTx) receptor mice to deplete CD11c+ cells during the priming stage of the CD4+ Th2 response against the parasitic helminth Schistosoma mansoni. DTx treatment significantly depleted CD11c+ DCs from all tissues tested, with 70–80% efficacy. Even this incomplete depletion resulted in dramatically impaired CD4+ T cell production of Th2 cytokines, altering the balance of the immune response and causing a shift toward IFN-γ production. In contrast, basophil depletion using Mar-1 antibody had no measurable effect on Th2 induction in this system. These data underline the vital role that CD11c+ antigen-presenting cells can play in orchestrating Th2 development against helminth infection in vivo, a response that is ordinarily balanced so as to prevent the potentially damaging production of inflammatory cytokines

Alternatively activated dendritic cells regulate CD4+ T-cell polarization in vitro and in vivo

Interleukin-4 is a cytokine widely known for its role in CD4(+) T cell polarization and its ability to alternatively activate macrophage populations. In contrast, the impact of IL-4 on the activation and function of dendritic cells (DCs) is poorly understood. We report here that DCs respond to IL-4 both in vitro and in vivo by expression of multiple alternative activation markers with a different expression pattern to that of macrophages. We further demonstrate a central role for DC IL-4Rα expression in the optimal induction of IFNγ responses in vivo in both Th1 and Th2 settings, through a feedback loop in which IL-4 promotes DC secretion of IL-12. Finally, we reveal a central role for RELMα during T-cell priming, establishing that its expression by DCs is critical for optimal IL-10 and IL-13 promotion in vitro and in vivo. Together, these data highlight the significant impact that IL-4 and RELMα can have on DC activation and function in the context of either bacterial or helminth pathogens

Impact of phenolic-rich olive leaf extract on blood pressure, plasma lipids and inflammatory markers: a randomised controlled trial

Purpose Dietary polyphenols have been demonstrated to favourably modify a number of cardiovascular risk markers such as blood pressure (BP), endothelial function and plasma lipids. We conducted a randomised, double-blind, controlled, crossover trial to investigate the effects of a phenolic-rich olive leaf extract (OLE) on BP and a number of associated vascular and metabolic measures. Methods A total of 60 pre-hypertensive [systolic blood pressure (SBP): 121–140 mmHg; diastolic blood pressure (DBP): 81–90 mmHg] males [mean age 45 (±SD 12.7 years, BMI 26.7 (±3.21) kg/m2] consumed either OLE (136 mg oleuropein; 6 mg hydroxytyrosol) or a polyphenol-free control daily for 6 weeks before switching to the alternate arm after a 4-week washout. Results Daytime [−3.95 (±SD 11.48) mmHg, p = 0.027] and 24-h SBP [−3.33 (±SD 10.81) mmHg, p = 0.045] and daytime and 24-h DBP [−3.00 (±SD 8.54) mmHg, p = 0.025; −2.42 (±SD 7.61) mmHg, p = 0.039] were all significantly lower following OLE intake, relative to the control. Reductions in plasma total cholesterol [−0.32 (±SD 0.70) mmol/L, p = 0.002], LDL cholesterol [−0.19 (±SD 0.56) mmol/L, p = 0.017] and triglycerides [−0.18 (±SD 0.48), p = 0.008] were also induced by OLE compared to control, whilst a reduction in interleukin-8 [−0.63 (±SD 1.13) pg/ml; p = 0.026] was also detected. Other markers of inflammation, vascular function and glucose metabolism were not affected. Conclusion Our data support previous research, suggesting that OLE intake engenders hypotensive and lipid-lowering effects in vivo

Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia

Background: The human pathogen Helicobacter pylori (H. pylori) is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention. Methodology/Principal Findings: We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map. Pharmacophoric features of the map are clustered and transformed in a correlation vector (‘virtual ligand’) for rapid virtual screening of compound databases. This computer-based technique was validated for 18 different targets of pharmaceutical interest in a retrospective screening experiment. Prospective screening for inhibitory agents was performed for the protease HtrA from the human pathogen H. pylori using a homology model of the target protein. Among 22 tested compounds six block E-cadherin cleavage by HtrA in vitro and result in reduced scattering and wound healing of gastric epithelial cells, thereby preventing bacterial infiltration of the epithelium. Conclusions/Significance: This study demonstrates that receptor-based virtual screening with a permissive (‘fuzzy’) pharmacophore model can help identify small bioactive agents for combating bacterial infection

Velocity-space sensitivity of the time-of-flight neutron spectrometer at JET

The velocity-space sensitivities of fast-ion diagnostics are often described by so-called weight functions. Recently, we formulated weight functions showing the velocity-space sensitivity of the often dominant beam-target part of neutron energy spectra. These weight functions for neutron emission spectrometry (NES) are independent of the particular NES diagnostic. Here we apply these NES weight functions to the time-of-flight spectrometer TOFOR at JET. By taking the instrumental response function of TOFOR into account, we calculate time-of-flight NES weight functions that enable us to directly determine the velocity-space sensitivity of a given part of a measured time-of-flight spectrum from TOFOR

Relationship of edge localized mode burst times with divertor flux loop signal phase in JET

A phase relationship is identified between sequential edge localized modes (ELMs) occurrence times in a set of H-mode tokamak plasmas to the voltage measured in full flux azimuthal loops in the divertor region. We focus on plasmas in the Joint European Torus where a steady H-mode is sustained over several seconds, during which ELMs are observed in the Be II emission at the divertor. The ELMs analysed arise from intrinsic ELMing, in that there is no deliberate intent to control the ELMing process by external means. We use ELM timings derived from the Be II signal to perform direct time domain analysis of the full flux loop VLD2 and VLD3 signals, which provide a high cadence global measurement proportional to the voltage induced by changes in poloidal magnetic flux. Specifically, we examine how the time interval between pairs of successive ELMs is linked to the time-evolving phase of the full flux loop signals. Each ELM produces a clear early pulse in the full flux loop signals, whose peak time is used to condition our analysis. The arrival time of the following ELM, relative to this pulse, is found to fall into one of two categories: (i) prompt ELMs, which are directly paced by the initial response seen in the flux loop signals; and (ii) all other ELMs, which occur after the initial response of the full flux loop signals has decayed in amplitude. The times at which ELMs in category (ii) occur, relative to the first ELM of the pair, are clustered at times when the instantaneous phase of the full flux loop signal is close to its value at the time of the first ELM

Sustained signaling by canonical helper T cell cytokines throughout the reactive lymph node

Cytokines are soluble proteins that regulate immune responses. The present paradigm is that cytokine production in lymphoid tissues is tightly localized and signaling occurs between conjugate cells. Here we assess cytokine signaling during infection by measuring in vivo phosphorylation of intracellular signal transducer and activator of transcription (STAT) proteins. We show that interferon-γ (IFN-γ) and interleukin 4 (IL-4) signaled to the majority of lymphocytes throughout the reactive lymph node and that IL-4 conditioning of naive, bystander cells was sufficient to override opposing T helper type 1 (TH1) polarization. Our results demonstrate that despite localized production, cytokines can permeate a lymph node and modify the majority of cells therein. Cytokine conditioning of bystander cells could provide a mechanism by which chronic worm infections subvert the host response to subsequent infections or vaccination attempts