Myeloid-derived suppressor cells (MDSC) play a crucial role in controlling T-cell responses, but their development and suppressor mechanisms are not fully understood. To study the molecular functions ...of MDSC, a large number of standardized cells are required. Traditionally, bone marrow (BM) has been used to generate myeloid cell types, including MDSC. In this study, we demonstrate that a previously described protocol for generating monocytic MDSC (M-MDSC) from murine BM with GM-CSF can be fully transferred to BM cells that are conditionally transformed with HoxB8 gene (HoxB8 cells). HoxB8 cells have an extended lifespan and efficiently differentiate into MDSC that are quantitatively and qualitatively comparable to M-MDSC from BM cells. Flow cytometric analyses of LPS/IFN-γ activated cultures revealed the same iNOS
and/or Arg1
PD-L1
M-MDSC subsets in similar frequencies from BM or HoxB8 cells. In vitro suppression of CD4
and CD8
T-cell proliferations was also largely comparable in their efficacy and its iNOS- or Arg1-dependent suppressor mechanisms, which was confirmed by the similar amounts of nitric oxide (NO) secretion measured from the suppressor assay. Therefore, our data suggest that murine M-MDSC generation from HoxB8 cells with GM-CSF can be used to substitute BM cultures.
Abstract The primary reference instruments for neutron fluence measurements used at the Physikalisch-Technische Bundesanstalt are based on the primary standard for neutron measurements which is the ...differential neutron–proton scattering cross section. Such instruments require considerable effort for their operation and analysis. Therefore, routine measurements are carried out using a transfer instrument to facilitate the efficient provision of services to customers. A series of measurements was conducted to compare the transfer device to the primary reference instruments and ensure the traceability of neutron fluence measurements. This resulted in an improved characterisation of the instrument and new analysis procedures. For neutron energies between 144 keV and 14.8 MeV, the ratio of neutron fluence values measured with the primary reference instruments and the transfer instrument deviates from unity by less than the estimated standard measurement uncertainties of 2.6% to 3.2%. At neutron energies between 30 keV and 100 keV, however, the experimental fluence ratios deviate from unity by about 4% which exceeds the estimated uncertainties of 2.5% to 2.9%. At present, the reason for this inconsistency remains unresolved.
The time characteristics of the surface charge accumulation process on cylindrical polymeric model insulators under dc stress were investigated in a partial discharge free, dry air environment. In ...order to simulate the influence of different dielectric and electric material properties on surface charge accumulation, a tool was developed which considers also the nonlinear behavior of the electric conduction mechanism within the gas volume. The results of simulation have been verified by measurements of the surface potential distribution along the samples at different ambient temperatures.
Dendritic cells (DCs) are currently divided into tolerogenic immature and immunogenic mature differentiation stages. However, recent findings challenge this model by reporting mature DCs as inducers ...of regulatory CD4
+ T cells
in vivo. This implies that decisive tolerogenic and immunogenic maturation signals for DCs might exist. Closer inspection reveals that tolerance is observed when partial- or semi-maturation of DCs occurs, whereas only full DC maturation is immunogenic. The decisive immunogenic signal seems to be the release of proinflammatory cytokines from the DCs. Moreover, the semi-mature DC phenotype is comparable to steady-state migratory veiled DCs within the lymphatics, which seem to continuously tolerize lymph node T cells against tissue-derived self-antigens or apoptotic cells.
Dendritic cells are currently divided into tolerogenic immature and immunogenic mature differentiation stages; however this model has been challenged by findings that decisive tolerogenic and immunogenic maturation signals might exist.
The COVID-19 pandemic and resulting measures can be regarded as a global stressor. Cross-sectional studies showed rather negative impacts on people's mental health, while longitudinal studies ...considering pre-lockdown data are still scarce. The present study investigated the impact of COVID-19 related lockdown measures in a longitudinal German sample, assessed since 2017. During lockdown, 523 participants completed additional weekly online questionnaires on e.g., mental health, COVID-19-related and general stressor exposure. Predictors for and distinct trajectories of mental health outcomes were determined, using multilevel models and latent growth mixture models, respectively. Positive pandemic appraisal, social support, and adaptive cognitive emotion regulation were positively, whereas perceived stress, daily hassles, and feeling lonely negatively related to mental health outcomes in the entire sample. Three subgroups ("recovered," 9.0%; "resilient," 82.6%; "delayed dysfunction," 8.4%) with different mental health responses to initial lockdown measures were identified. Subgroups differed in perceived stress and COVID-19-specific positive appraisal. Although most participants remained mentally healthy, as observed in the resilient group, we also observed inter-individual differences. Participants' psychological state deteriorated over time in the delayed dysfunction group, putting them at risk for mental disorder development. Consequently, health services should especially identify and allocate resources to vulnerable individuals.
Monocytes and cells of the dendritic cell lineage circulate in blood and eventually migrate into tissue where they further mature and serve various functions, most notably in immune defense. Over ...recent years these cells have been characterized in detail with the use of cell surface markers and flow cytometry, and subpopulations have been described. The present document proposes a nomenclature for these cells and defines 3 types of monocytes (classical, intermediate, and nonclassical monocytes) and 3 types of dendritic cells (plasmacytoid and 2 types of myeloid dendritic cells) in human and in mouse blood. This classification has been approved by the Nomenclature Committee of the International Union of Immunological Societies, and we are convinced that it will facilitate communication among experts and in the wider scientific community.
In a recent article (Helft et al., 2015), murine bone marrow (BM) cultures with granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed for macrophage (“GM-Mac”) and dendritic cell ...(“GM-DC”) subsets, and the GM-DC subset was compared with conventional or classical DC (cDC) subsets isolated from peripheral and lymphoid organs of mice. The article was accompanied by a preview about the usefulness of murine BM-DC cultures in the study of DC biology (Guilliams and Malissen, 2015), insinuating that BM-DCs are not real DCs. But what is a real DC? To reanimate the “DC-ness” of murine BM-DCs, we collected some additional points that have not been addressed by recent papers or comments. We suggest their consideration for further discussion.
In a recent article (Helft et al., 2015), murine bone marrow (BM) cultures with granulocyte-macrophage colony-stimulating factor (GM-CSF) were analyzed for macrophage (“GM-Mac”) and dendritic cell (“GM-DC”) subsets, and the GM-DC subset was compared with conventional or classical DC (cDC) subsets isolated from peripheral and lymphoid organs of mice. The article was accompanied by a preview about the usefulness of murine BM-DC cultures in the study of DC biology (Guilliams and Malissen, 2015), insinuating that BM-DCs are not real DCs. But what is a real DC? To reanimate the “DC-ness” of murine BM-DCs, we collected some additional points that have not been addressed by recent papers or comments. We suggest their consideration for further discussion.
The CB1 cannabinoid receptor, the main molecular target of endocannabinoids and cannabis active components, is the most abundant G protein-coupled receptor in the mammalian brain. In particular, the ...CB1 receptor is highly expressed in the basal ganglia, mostly on terminals of medium-sized spiny neurons, where it plays a key neuromodulatory function. The CB1 receptor also confers neuroprotection in various experimental models of striatal damage. However, the assessment of the physiological relevance and therapeutic potential of the CB1 receptor in basal ganglia-related diseases is hampered, at least in part, by the lack of knowledge of the precise mechanism of CB1 receptor neuroprotective activity. Here, by using an array of pharmacological, genetic and pharmacogenetic (designer receptor exclusively activated by designer drug) approaches, we show that (1) CB1 receptor engagement protects striatal cells from excitotoxic death via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin complex 1 pathway, which, in turn, (2) induces brain-derived neurotrophic factor (BDNF) expression through the selective activation of BDNF gene promoter IV, an effect that is mediated by multiple transcription factors. To assess the possible functional impact of the CB1/BDNF axis in a neurodegenerative-disease context in vivo, we conducted experiments in the R6/2 mouse, a well-established model of Huntington's disease, in which the CB1 receptor and BDNF are known to be severely downregulated in the dorsolateral striatum. Adeno-associated viral vector-enforced re-expression of the CB1 receptor in the dorsolateral striatum of R6/2 mice allowed the re-expression of BDNF and the concerted rescue of the neuropathological deficits in these animals. Collectively, these findings unravel a molecular link between CB1 receptor activation and BDNF expression, and support the relevance of the CB1/BDNF axis in promoting striatal neuron survival.
Evidence for the involvement of the endocannabinoid system (ECS) in anxiety and fear has been accumulated, providing leads for novel therapeutic approaches. In anxiety, a bidirectional influence of ...the ECS has been reported, whereby anxiolytic and anxiogenic responses have been obtained after both increases and decreases of the endocannabinoid tone. The recently developed genetic tools have revealed different but complementary roles for the cannabinoid type 1 (CB1) receptor on GABAergic and glutamatergic neuronal populations. This dual functionality, together with the plasticity of CB1 receptor expression, particularly on GABAergic neurons, as induced by stressful and rewarding experiences, gives the ECS a unique regulatory capacity for maintaining emotional homeostasis. However, the promiscuity of the endogenous ligands of the CB1 receptor complicates the interpretation of experimental data concerning ECS and anxiety. In fear memory paradigms, the ECS is mostly involved in the two opposing processes of reconsolidation and extinction of the fear memory. Whereas ECS activation deteriorates reconsolidation, proper extinction depends on intact CB1 receptor signalling. Thus, both for anxiety and fear memory processing, endocannabinoid signalling may ensure an appropriate reaction to stressful events. Therefore, the ECS can be considered as a regulatory buffer system for emotional responses.
Dendritic cells (DCs) are major players in the control of adaptive tolerance and immunity. Therefore, their specific generation and adoptive transfer into patients or their in vivo targeting is ...attractive for clinical applications. While injections of mature immunogenic DCs are tested in clinical trials, tolerogenic DCs still are awaiting this step. Besides the tolerogenic potential of immature DCs, also semi-mature DCs can show tolerogenic activity but both types also bear unfavorable features. Optimal tolerogenic DCs, their molecular tool bar, and their use for specific diseases still have to be defined. Here, the usefulness of in vitro generated and adoptively transferred semi-mature DCs for tolerance induction is outlined. The in vivo targeting of semi-mature DCs as represented by steady state migratory DCs are discussed for treatment of autoimmune diseases and allergies. First clinical trials with transcutaneous allergen application may point to their therapeutic use in the future.
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