Effects of a dual CCR3 and H1-antagonist on symptoms and eosinophilic inflammation in allergic rhinitis

<p>Abstract</p> <p>Background</p> <p>The CC-chemokine receptor-3 (CCR3) has emerged as a target molecule for pharmacological intervention in allergic inflammation.</p> <p>Objective</p> <p>To examine whether a dual CCR3 and H₁-receptor antagonist (AZD3778) affects allergic inflammation and symptoms in allergic rhinitis.</p> <p>Methods</p> <p>Patients with seasonal allergic rhinitis were subjected to three seven days' allergen challenge series. Treatment with AZD3778 was given in a placebo and antihistamine-controlled design. Symptoms and nasal peak inspiratory flow (PIF) were monitored in the morning, ten minutes post challenge, and in the evening. Nasal lavages were carried out at the end of each challenge series and α₂-macroglobulin, ECP, and tryptase were monitored as indices of allergic inflammation.</p> <p>Results</p> <p>Plasma levels of AZD3778 were stable throughout the treatment series. AZD3778 and the antihistamine (loratadine) reduced rhinitis symptoms recorded ten minutes post challenge during this period. AZD3778, but not the anti-histamine, also improved nasal PIF ten minutes post challenge. Furthermore, scores for morning and evening nasal symptoms from the last five days of the allergen challenge series showed statistically significant reductions for AZD3778, but not for loratadine. ECP was reduced by AZD3778, but not by loratadine.</p> <p>Conclusions</p> <p>AZD3778 exerts anti-eosinophil and symptom-reducing effects in allergic rhinitis and part of this effect can likely be attributed to CCR3-antagonism. The present data are of interest with regard to the potential use of AZD3778 in allergic rhinitis and to the relative importance of eosinophil actions to the symptomatology of allergic rhinitis.</p> <p>Trial registration</p> <p>EudraCT No: 2005-002805-21.</p

Role of lysophosphatidic acid receptor LPA2 in the development of allergic airway inflammation in a murine model of asthma

<p>Abstract</p> <p>Background</p> <p>Lysophosphatidic acid (LPA) plays a critical role in airway inflammation through G protein-coupled LPA receptors (LPA_1-3). We have demonstrated that LPA induced cytokine and lipid mediator release in human bronchial epithelial cells. Here we provide evidence for the role of LPA and LPA receptors in Th2-dominant airway inflammation.</p> <p>Methods</p> <p/> <p>Wild type, LPA₁heterozygous knockout mice (LPA₁^+/-), and LPA₂heterozygous knockout mice (LPA₂^+/-) were sensitized with inactivated <it>Schistosoma mansoni </it>eggs and local antigenic challenge with <it>Schistosoma mansoni </it>soluble egg Ag (SEA) in the lungs. Bronchoalveolar larvage (BAL) fluids and lung tissues were collected for analysis of inflammatory responses. Further, tracheal epithelial cells were isolated and challenged with LPA.</p> <p>Results</p> <p>BAL fluids from <it>Schistosoma mansoni </it>egg-sensitized and challenged wild type mice (4 days of challenge) showed increase of LPA level (~2.8 fold), compared to control mice. LPA₂^+/-mice, but not LPA₁^+/-mice, exposed to <it>Schistosoma mansoni </it>egg revealed significantly reduced cell numbers and eosinophils in BAL fluids, compared to challenged wild type mice. Both LPA₂^+/-and LPA₁^+/-mice showed decreases in bronchial goblet cells. LPA₂^+/-mice, but not LPA₁^+/-mice showed the decreases in prostaglandin E2 (PGE2) and LPA levels in BAL fluids after SEA challenge. The PGE2 production by LPA was reduced in isolated tracheal epithelial cells from LPA₂^+/-mice. These results suggest that LPA and LPA receptors are involved in <it>Schistosoma mansoni </it>egg-mediated inflammation and further studies are proposed to understand the role of LPA and LPA receptors in the inflammatory process.</p

Cysteinyl leukotrienes: multi-functional mediators in allergic rhinitis

Cysteinyl leukotrienes (CysLTs) are a family of inflammatory lipid mediators synthesized from arachidonic acid by a variety of cells, including mast cells, eosinophils, basophils, and macrophages. This article reviews the data for the role of CysLTs as multi-functional mediators in allergic rhinitis (AR). We review the evidence that: (1) CysLTs are released from inflammatory cells that participate in AR, (2) receptors for CysLTs are located in nasal tissue, (3) CysLTs are increased in patients with AR and are released following allergen exposure, (4) administration of CysLTs reproduces the symptoms of AR, (5) CysLTs play roles in the maturation, as well as tissue recruitment, of inflammatory cells, and (6) a complex inter-regulation between CysLTs and a variety of other inflammatory mediators exists.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/75432/1/j.1365-2222.2006.02498.x.pd

Eosinophils in glioblastoma biology

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. The development of this malignant glial lesion involves a multi-faceted process that results in a loss of genetic or epigenetic gene control, un-regulated cell growth, and immune tolerance. Of interest, atopic diseases are characterized by a lack of immune tolerance and are inversely associated with glioma risk. One cell type that is an established effector cell in the pathobiology of atopic disease is the eosinophil. In response to various stimuli, the eosinophil is able to produce cytotoxic granules, neuromediators, and pro-inflammatory cytokines as well as pro-fibrotic and angiogenic factors involved in pathogen clearance and tissue remodeling and repair. These various biological properties reveal that the eosinophil is a key immunoregulatory cell capable of influencing the activity of both innate and adaptive immune responses. Of central importance to this report is the observation that eosinophil migration to the brain occurs in response to traumatic brain injury and following certain immunotherapeutic treatments for GBM. Although eosinophils have been identified in various central nervous system pathologies, and are known to operate in wound/repair and tumorstatic models, the potential roles of eosinophils in GBM development and the tumor immunological response are only beginning to be recognized and are therefore the subject of the present review

Scintillation light detection in the 6-m drift-length ProtoDUNE Dual Phase liquid argon TPC

DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6  ×  6  ×  6 m 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019-2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties

Design, construction and operation of the ProtoDUNE-SP Liquid Argon TPC

The ProtoDUNE-SP detector is a single-phase liquid argon time projection chamber (LArTPC) that was constructed and operated in the CERN North Area at the end of the H4 beamline. This detector is a prototype for the first far detector module of the Deep Underground Neutrino Experiment (DUNE), which will be constructed at the Sandford Underground Research Facility (SURF) in Lead, South Dakota, U.S.A. The ProtoDUNE-SP detector incorporates full-size components as designed for DUNE and has an active volume of 7 × 6 × 7.2 m3. The H4 beam delivers incident particles with well-measured momenta and high-purity particle identification. ProtoDUNE-SP's successful operation between 2018 and 2020 demonstrates the effectiveness of the single-phase far detector design. This paper describes the design, construction, assembly and operation of the detector components

Separation of track- and shower-like energy deposits in ProtoDUNE-SP using a convolutional neural network

Liquid argon time projection chamber detector technology provides high spatial and calorimetric resolutions on the charged particles traversing liquid argon. As a result, the technology has been used in a number of recent neutrino experiments, and is the technology of choice for the Deep Underground Neutrino Experiment (DUNE). In order to perform high precision measurements of neutrinos in the detector, final state particles need to be effectively identified, and their energy accurately reconstructed. This article proposes an algorithm based on a convolutional neural network to perform the classification of energy deposits and reconstructed particles as track-like or arising from electromagnetic cascades. Results from testing the algorithm on data from ProtoDUNE-SP, a prototype of the DUNE far detector, are presented. The network identifies track- and shower-like particles, as well as Michel electrons, with high efficiency. The performance of the algorithm is consistent between data and simulation

Separation of track- and shower-like energy deposits in ProtoDUNE-SP using a convolutional neural network

Liquid argon time projection chamber detector technology provides high spatial and calorimetric resolutions on the charged particles traversing liquid argon. As a result, the technology has been used in a number of recent neutrino experiments, and is the technology of choice for the Deep Underground Neutrino Experiment (DUNE). In order to perform high precision measurements of neutrinos in the detector, final state particles need to be effectively identified, and their energy accurately reconstructed. This article proposes an algorithm based on a convolutional neural network to perform the classification of energy deposits and reconstructed particles as track-like or arising from electromagnetic cascades. Results from testing the algorithm on experimental data from ProtoDUNE-SP, a prototype of the DUNE far detector, are presented. The network identifies track- and shower-like particles, as well as Michel electrons, with high efficiency. The performance of the algorithm is consistent between experimental data and simulation

Low exposure long-baseline neutrino oscillation sensitivity of the DUNE experiment

The Deep Underground Neutrino Experiment (DUNE) will produce world-leading neutrino oscillation measurements over the lifetime of the experiment. In this work, we explore DUNE's sensitivity to observe charge-parity violation (CPV) in the neutrino sector, and to resolve the mass ordering, for exposures of up to 100 kiloton-megawatt-years (kt-MW-yr). The analysis includes detailed uncertainties on the flux prediction, the neutrino interaction model, and detector effects. We demonstrate that DUNE will be able to unambiguously resolve the neutrino mass ordering at a 3σ (5σ) level, with a 66 (100) kt-MW-yr far detector exposure, and has the ability to make strong statements at significantly shorter exposures depending on the true value of other oscillation parameters. We also show that DUNE has the potential to make a robust measurement of CPV at a 3σ level with a 100 kt-MW-yr exposure for the maximally CP-violating values \delta_{\rm CP}} = \pm\pi/2. Additionally, the dependence of DUNE's sensitivity on the exposure taken in neutrino-enhanced and antineutrino-enhanced running is discussed. An equal fraction of exposure taken in each beam mode is found to be close to optimal when considered over the entire space of interest