734 research outputs found
Immune modulation via T regulatory cell enhancement:Disease-modifying therapies for autoimmunity and their potential for chronic allergic and inflammatory diseases-An EAACI position paper of the Task Force on Immunopharmacology (TIPCO)
Therapeutic advances using targeted biologicals and small-molecule drugs have achieved significant success in the treatment of chronic allergic, autoimmune, and inflammatory diseases particularly for some patients with severe, treatment-resistant forms. This has been aided by improved identification of disease phenotypes. Despite these achievements, not all severe forms of chronic inflammatory and autoimmune diseases are successfully targeted, and current treatment options, besides allergen immunotherapy for selected allergic diseases, fail to change the disease course. T cellâbased therapies aim to cure diseases through the selective induction of appropriate immune responses following the delivery of engineered, specific cytotoxic, or regulatory T cells (Tregs). Adoptive cell therapies (ACT) with genetically engineered T cells have revolutionized the oncology field, bringing curative treatment for leukemia and lymphoma, while therapies exploiting the suppressive functions of Tregs have been developed in nononcological settings, such as in transplantation and autoimmune diseases. ACT with Tregs are also being considered in nononcological settings such as cardiovascular disease, obesity, and chronic inflammatory disorders. After describing the general features of T cellâbased approaches and current applications in autoimmune diseases, this position paper reviews the experimental models testing or supporting T cellâbased approaches, especially Treg-based approaches, in severe IgE-mediated responses and chronic respiratory airway diseases, such as severe asthma and COPD. Along with an assessment of challenges and unmet needs facing the application of ACT in these settings, this article underscores the potential of ACT to offer curative options for patients with severe or treatment-resistant forms of these immune-driven disorders
Metabolic pathways in immune senescence and inflammaging: Novel therapeutic strategy for chronic inflammatory lung diseases. An EAACI position paper from the Task Force for Immunopharmacology
The accumulation of senescent cells drives inflammaging and increases morbidity of chronic inflammatory lung diseases. Immune responses are built upon dynamic changes in cell metabolism that supply energy and substrates for cell proliferation, differentiation, and activation. Metabolic changes imposed by environmental stress and inflammation on immune cells and tissue microenvironment are thus chiefly involved in the pathophysiology of allergic and other immuneâdriven diseases. Altered cell metabolism is also a hallmark of cell senescence, a condition characterized by loss of proliferative activity in cells that remain metabolically active. Accelerated senescence can be triggered by acute or chronic stress and inflammatory responses. In contrast, replicative senescence occurs as part of the physiological aging process and has protective roles in cancer surveillance and wound healing. Importantly, cell senescence can also change or hamper response to diverse therapeutic treatments. Understanding the metabolic pathways of senescence in immune and structural cells is therefore critical to detect, prevent, or revert detrimental aspects of senescenceârelated immunopathology, by developing specific diagnostics and targeted therapies. In this paper, we review the main changes and metabolic alterations occurring in senescent immune cells (macrophages, B cells, T cells). Subsequently, we present the metabolic footprints described in translational studies in patients with chronic asthma and chronic obstructive pulmonary disease (COPD), and review the ongoing preclinical studies and clinical trials of therapeutic approaches aiming at targeting metabolic pathways to antagonize pathological senescence. Because this is a recently emerging field in allergy and clinical immunology, a better understanding of the metabolic profile of the complex landscape of cell senescence is needed. The progress achieved so far is already providing opportunities for new therapies, as well as for strategies aimed at disease prevention and supporting healthy aging
Stateâofâtheâart in marketed adjuvants and formulations in Allergen Immunotherapy: a position paper of the European Academy of Allergy and Clinical Immunology (EAACI)
Since the introduction of allergen immunotherapy (AIT) over 100 years ago, focus has been on standardization of allergen extracts, with reliable molecular composition of allergens receiving the highest attention. While adjuvants play a major role in European AIT, they have been less well studied. In this Position Paper we summarize current unmet needs of adjuvants in AIT citing current evidence. Four adjuvants are used in products marketed in Europe: aluminium hydroxide (Al(OH)3) is the most frequently used adjuvant, with microcrystalline tyrosine (MCT), monophosphoryl lipid A (MPLA) and calcium phosphate (CaP) used less frequently. Recent studies on humans, and using mouse models, have characterized in part the mechanisms of action of adjuvants on preâexisting immune responses. AIT differs from prophylactic vaccines that provoke immunity to infectious agents, as in allergy the patient is preâsensitized to the allergen. The intended mode of action of adjuvants is to simultaneously enhance the immunogenicity of the allergen, while precipitating the allergen at the injection site to reduce the risk of anaphylaxis. Contrasting immune effects are seen with different adjuvants. Aluminium hydroxide initially boosts Th2 responses, while the other adjuvants utilised in AIT redirect the Th2 immune response toward Th1 immunity. After varying lengths of time, each of the adjuvants supports tolerance. Further studies of the mechanisms of action of adjuvants may advise shorter treatment periods than the current threeâtoâfiveâyear regimens, enhancing patient adherence. Improved lead compounds from the adjuvant pipeline are under development and are explored for their capacity to fill this unmet need
Spontaneous left main coronary artery dissection complicated by pseudoaneurysm formation in pregnancy: role of CT coronary angiography
We report a case of a 26-year-old female, who presented at 34 weeks of an uncomplicated pregnancy with an acute ST elevation anterior wall myocardial infarction. Cardiac catheterization suggested a left main coronary artery dissection with pseudoaneurysm formation. The patient's course was complicated by congestive heart failure. She was initially managed conservatively by a multidisciplinary team including heart failure specialists, obstetricians, and cardiovascular surgeons. 4 days after admission, her LMC was imaged by dual-source 64 slice Cardiac computed tomography, coronary dissection was identified extending to the lumen, and the presence of pseudoaneurysm was confirmed. She underwent subsequently a staged procedure, which included placement of an intra-aortic balloon pump, cesarean section, and coronary artery bypass grafting. This case illustrates the utility of coronary artery CT imaging to assess the complexity and stability of coronary artery dissections, thereby helping to determine the need for, and timing of revascularization procedures
Energy-dependent light quenching in CaWO4 crystals at mK temperatures
Scintillating CaWO4 single crystals are a promising multi-element target for rare-event searches and are currently used in the direct dark matter experiment CRESST (Cryogenic Rare Event Search with Superconducting Thermometers). The relative light output of different particle interactions in CaWO4 is quantified by quenching factors (QFs). These are essential for an active background discrimination and the identification of a possible signal induced by weakly interacting massive particles (WIMPs). We present the first precise measurements of the QFs of O, Ca and W at mK temperatures by irradiating a cryogenic detector with a fast neutron beam. A clear energy dependence of the QF of O and, less pronounced, of Ca was observed for the first time. Furthermore, in CRESST neutron-calibration data a variation of the QFs among different CaWO4 single crystals was found. For typical CRESS
Binding to Iron Quercetin Complexes Increases the Antioxidant Capacity of the Major Birch Pollen Allergen Bet v 1 and Reduces Its Allergenicity
Bet v 1 is the major allergen in birch pollen to which up to 95% of patients sensitized to birch respond. As a member of the pathogenesis-related PR 10 family, its natural function is implicated in plant defense, with a member of the PR10 family being reported to be upregulated under iron deficiency. As such, we assessed the function of Bet v 1 to sequester iron and its immunomodulatory properties on human immune cells. Binding of Bet v 1 to iron quercetin complexes FeQ2 was determined in docking calculations and by spectroscopy. Serum IgE-binding to Bet v 1 with (holoBet v1) and without ligands (apoBet v 1) were assessed by ELISA, blocking experiments and Western Blot. Crosslinking-capacity of apo/holoBet v 1 were assessed on human mast cells and Arylhydrocarbon receptor (AhR) activation with the human reporter cellline AZ-AHR. Human PBMCs were stimulated and assessed for labile iron and phenotypic changes by flow cytometry. Bet v 1 bound to FeQ2 strongly with calculated Kd values of 1 nm surpassing affinities to quercetin alone nearly by a factor of 1000. Binding to FeQ2 masked IgE epitopes and decreased IgE binding up to 80% and impaired degranulation of sensitized human mast cells. Bet v 1 facilitated the shuttling of quercetin, which activated the anti-inflammatory AhR pathway and increased the labile iron pool of human monocytic cells. The increase of labile iron was associated with an anti-inflammatory phenotype in CD14+monocytes and downregulation of HLADR. To summarize, we reveal for the first time that FeQ2 binding reduces the allergenicity of Bet v 1 due to ligand masking, but also actively contributes anti-inflammatory stimuli to human monocytes, thereby fostering tolerance. Nourishing immune cells with complex iron may thus represent a promising antigen-independent immunotherapeutic approach to improve efficacy in allergen immunotherapy
The human polyomavirus, JCV, uses serotonin receptors to infect cells
The human polyomavirus, JCV, causes the fatal demyelinating disease progressive multifocal leukoencephalopathy in immunocompromised patients. We found that the serotonergic receptor 5HT2AR could act as the cellular receptor for JCV on human glial cells. The 5HT2Areceptor antagonists inhibited JCV infection, and monoclonal antibodies directed at 5HT2Areceptors blocked infection of glial cells by JCV, but not by SV40. Transfection of 5HT2Areceptorânegative HeLa cells with a 5HT2A receptor rescued virus infection, and this infection was blocked by antibody to the 5HT2A receptor. A tagged 5HT2A receptor colocalized with labeled JCV in an endosomal compartment following internalization. Serotonin receptor antagonists may thus be useful in the treatment of progressive multifocal leukoencephalopathy
Two-dimensional H_alpha kinematics of bulgeless disk galaxies
We present two-dimensional H_alpha velocity fields for 20 late-type,
disk-dominated spiral galaxies, the largest sample to date with high-resolution
H_alpha velocity fields for bulgeless disks. From these data we derive rotation
curves and the location of the kinematic centers. The galaxy sample was
selected to contain nucleated and non-nucleated galaxies, which allows us to
investigate what impact the gas kinematics in the host disk have on the
presence (or absence) of a nuclear star cluster. In general, we find that the
velocity fields span a broad range of morphologies. While some galaxies show
regular rotation, most have some degree of irregular gas motions. There appears
to be no systematic difference in the kinematics of nucleated and non-nucleated
disks. Due to the large fields of view of the integral field units we use, we
are able to observe the flattening of the rotation curve in almost all of our
sample galaxies. This makes modeling of the velocity fields relatively
straight-forward. Due to the complexities of the velocity fields, we obtain
reliable determinations of the kinematic center for only 6 of our 20 sample
galaxies. For all of these the locations of the nuclear star
cluster/photometric center and the kinematic center agree within the
uncertainties. If we disregard all kinematically irregular galaxies, our study
concludes that nuclear star clusters truly occupy the nuclei, or dynamical
centers, of their hosts. Our results are thus consistent with in-situ formation
of nuclear star clusters. Yet, many well-motivated formation scenarios for
nuclear clusters invoke off-center cluster formation and subsequent sinking of
clusters due to dynamical friction. In that case, our results imply that
dynamical friction in the centers of bulgeless galaxies must be very effective
in driving massive clusters to the kinematic center. (abridged)Comment: 16 pages, 7 figures(some in reduced quality); MNRAS in pres
Lateral Distribution of Muons in IceCube Cosmic Ray Events
In cosmic ray air showers, the muon lateral separation from the center of the
shower is a measure of the transverse momentum that the muon parent acquired in
the cosmic ray interaction. IceCube has observed cosmic ray interactions that
produce muons laterally separated by up to 400 m from the shower core, a factor
of 6 larger distance than previous measurements. These muons originate in high
pT (> 2 GeV/c) interactions from the incident cosmic ray, or high-energy
secondary interactions. The separation distribution shows a transition to a
power law at large values, indicating the presence of a hard pT component that
can be described by perturbative quantum chromodynamics. However, the rates and
the zenith angle distributions of these events are not well reproduced with the
cosmic ray models tested here, even those that include charm interactions. This
discrepancy may be explained by a larger fraction of kaons and charmed
particles than is currently incorporated in the simulations
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