Grass pollen injection immunotherapy: Time course of suppression of allergen-induced late-phase skin responses

2005 ◽  
Vol 115 (2) ◽  
pp. S266 ◽  
Author(s):  
G. Paraskevopoulos ◽  
M.R. Jacobson ◽  
V. Carr ◽  
M. Calderon ◽  
S.J. Till ◽  
...  
Keyword(s):  
Grass Pollen ◽  
Time Course ◽  
Late Phase ◽  
Skin Responses

scholarly journals A randomised placebo-controlled trial investigating efficacy and mechanisms of low-dose intradermal allergen immunotherapy in treatment of seasonal allergic rhinitis

2016 ◽  
Vol 3 (10) ◽  
pp. 1-80
Author(s):  
Anna Slovick ◽  
Abdel Douiri ◽  
Rachel Muir ◽  
Andrea Guerra ◽  
Konstantinos Tsioulos ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Allergic Rhinitis ◽  
Grass Pollen ◽  
Low Dose ◽  
Late Phase ◽  
Phl P 5 ◽  
Skin Responses ◽  
Skin Biopsies ◽  
Immunological Priming

BackgroundWe previously reported that repeated low-dose grass pollen intradermal allergen injection suppresses allergen-induced cutaneous late-phase responses, comparable with conventional high-dose subcutaneous and sublingual immunotherapy.ObjectiveTo evaluate the efficacy and mechanism of grass pollen intradermal immunotherapy for treatment of allergic rhinitis.DesignA Phase II, double-blind, randomised controlled parallel-group trial.SettingSingle-centre UK study.ParticipantsAdults aged 18–65 years, with grass pollen-induced allergic rhinoconjunctivitis.InterventionsSeven 2-weekly intradermal injections were given into the forearm, containing eitherPhleum pratensesoluble grass pollen extract (7 ng of the major allergen Phl p 5) or histamine control.Main outcome measuresThe primary outcome was a combined symptom and medication score (CSMS) during the 2013 grass pollen season. Secondary clinical outcomes were overall symptom scores; individual symptoms scores for nose, mouth, eyes and lungs; overall medication scores; CSMSs during the peak season; visual analogue scale (VAS) scores for nose and eye symptoms; Mini Rhinitis Quality of Life Questionnaire scores; health-related quality-of-life scores (European Quality of Life-5 Dimensions, 5-levels); a global evaluation of symptoms, number of symptom-free and medication-free days; number of days when prednisolone was used; and adverse events. Mechanistic studies included measurement of late-phase skin response sizes, allergen-specific antibody titres, analysis of skin biopsies and basophil activation tests.ResultsThere was no significant difference in CSMSs between treatment arms [difference in median area under curve (AUC) 14, 95% confidence interval (CI) –172.5 to 215.1;p = 0.80]. Paradoxically, among the secondary outcomes, nasal symptoms measured with daily scores were higher in the active arm (difference in median AUC 35, 95% CI 4.0 to 67.5;p = 0.03), with a trend for higher nasal symptoms measured by VASs (difference in median AUC 53, 95% CI –11.6 to 125.2;p = 0.05). No differences were seen in other clinical outcomes in the main intention-to-treat analysis. In mechanistic studies, active treatment increasedP. pratense-, Phl p 1- and Phl p 5-specific immunoglobulin E (allp = 0.001) compared with the control. T cells cultured from skin biopsies of active intradermal immunotherapy subjects showed higher T helper type 2 cell (Th2) marker CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells) expression (p < 0.05) and lower T helper type 1 cell marker CXCR3 [chemokine (C-X-C Motif) receptor 3] expression (p < 0.05), respectively. Interleukin 5 messenger ribonucleic acid, measured by microarray, was more highly expressed by cultured skin T cells in the active arm (p < 0.05). Late-phase skin responses to grass pollen were still inhibited up to 7 months after intradermal immunotherapy (p = 0.03), but not at 10–13 months’ time points.LimitationsGrass pollen doses were not increased during the course, as our proof-of-concept trial showed that repeating the same doses was sufficient to achieve almost complete late-response suppression. Injections were not continued throughout the season, as previous subcutaneous grass pollen immunotherapy trials have demonstrated preseasonal regimen efficacy.ConclusionsIntradermal immunotherapy suppressed late-phase skin responses to allergen, but was not clinically effective. The intervention appeared to have an immunological priming effect and exacerbated certain seasonal symptoms, notably in the nose.Future workFurther studies on low-dose intradermal grass pollen immunotherapy are not recommended because of our demonstrated worsening of allergic rhinitis symptoms and immunological priming. The findings are of great significance for other novel immunotherapies targeting the skin, such as epicutaneous techniques.Trial registrationCurrent Controlled Trials ISRCTN78413121.FundingThis project was funded by the Efficacy and Mechanism Evaluation programme, a Medical Research Council and National Institute for Health Research partnership.

scholarly journals Decoding the temporal nature of brain GR activity in the NFκB signal transition leading to depressive-like behavior

2021 ◽  
Author(s):  
Young-Min Han ◽  
Min Sun Kim ◽  
Juyeong Jo ◽  
Daiha Shin ◽  
Seung-Hae Kwon ◽  
...  
Keyword(s):  
Inhibitory Action ◽  
Time Course ◽  
Molecular Mechanisms ◽  
Late Phase ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Middle Phase ◽  
Temporal Shift

AbstractThe fine-tuning of neuroinflammation is crucial for brain homeostasis as well as its immune response. The transcription factor, nuclear factor-κ-B (NFκB) is a key inflammatory player that is antagonized via anti-inflammatory actions exerted by the glucocorticoid receptor (GR). However, technical limitations have restricted our understanding of how GR is involved in the dynamics of NFκB in vivo. In this study, we used an improved lentiviral-based reporter to elucidate the time course of NFκB and GR activities during behavioral changes from sickness to depression induced by a systemic lipopolysaccharide challenge. The trajectory of NFκB activity established a behavioral basis for the NFκB signal transition involved in three phases, sickness-early-phase, normal-middle-phase, and depressive-like-late-phase. The temporal shift in brain GR activity was differentially involved in the transition of NFκB signals during the normal and depressive-like phases. The middle-phase GR effectively inhibited NFκB in a glucocorticoid-dependent manner, but the late-phase GR had no inhibitory action. Furthermore, we revealed the cryptic role of basal GR activity in the early NFκB signal transition, as evidenced by the fact that blocking GR activity with RU486 led to early depressive-like episodes through the emergence of the brain NFκB activity. These results highlight the inhibitory action of GR on NFκB by the basal and activated hypothalamic-pituitary-adrenal (HPA)-axis during body-to-brain inflammatory spread, providing clues about molecular mechanisms underlying systemic inflammation caused by such as COVID-19 infection, leading to depression.

Late pulmonary responses induced by Ascaris allergen in conscious squirrel monkeys

1986 ◽  
Vol 61 (6) ◽  
pp. 2081-2087 ◽  
Author(s):  
R. Hamel ◽  
C. S. McFarlane ◽  
A. W. Ford-Hutchinson
Keyword(s):  
Time Course ◽  
Late Phase ◽  
Dynamic Compliance ◽  
Negative Control ◽  
Squirrel Monkeys ◽  
Antigen Challenge ◽  
Late Response ◽  
Primate Model ◽  
Positive Skin ◽  
Pulmonary Response

This study presents an antigen-dependent model of biphasic pulmonary changes to Ascaris suum in conscious squirrel monkeys. Animals with strong positive skin reactivity towards A. suum were trained to sit quietly in chairs and to breathe through face masks. Dynamic compliance (Cdyn) and pulmonary resistance (RL) were measured in these conscious animals before and for a period of 11 h after administration of an aerosol of Ascaris or ragweed antigen. The aerosol of Ascaris antigen induced reproducible increases (42%) in RL (P less than 0.001) and decreases (17%) in Cdyn (P less than 0.01) that peaked respectively 5 and 35 min after antigen challenge and lasted 60–90 min. After recovery, a second bronchoconstriction began between 2 and 8 h and peaked between 4 and 10 h after antigen challenge. Decreases in Cdyn (41%) were significantly greater (P less than 0.003) whereas mean increases in RL (44%) were similar during the late phase as compared with the first phase. The mean Cdyn decreases lasted a minimum of 2 h, whereas RL increases lasted less than 60 min. The time course of the responses varied from animal to animal but changes in individual animals were reproducible over a period of 6 mo. No significant correlation was observed between the cutaneous and the pulmonary responses to Ascaris and the late response was not reversed by aerosol administration of salbutamol (1.0 mg/ml). As a negative control animals were exposed to an aerosol of ragweed extract after which no immediate or late pulmonary response were observed. The results suggest that this primate model may be useful to study the pathophysiology of asthma in humans.

The dynamics of antibody-induced redistribution of viral envelope antigens in the plasma membranes of avian tumour virus-infected chick embryo fibroblasts

1976 ◽  
Vol 20 (3) ◽  
pp. 459-477
Author(s):  
E.R. Phillips ◽  
J.F. Perdue
Keyword(s):  
Chick Embryo ◽  
Time Course ◽  
Plasma Membranes ◽  
Late Phase ◽  
Viral Envelope ◽  
Microtubule Assembly ◽  
Electron Microscopic ◽  
Peripheral Cell ◽  
Thin Sections ◽  
Embryo Fibroblasts

Avian tumour virus-infected chick embryo fibroblasts express new antigens, identical with the viral envelope antigens, in their plasma membranes. Electron-microscopic examination of carbon-platinum replicas of cells labelled with haemocyanin-marked antibody has shown the distribution of these antigens to be diffuse over the cell surface with an increased concentration on peripheral cell processes. However, antigen-antibody complexes (AAC), resulting from reaction with specific antibody, may be redistributed into a variety of patterns. Observation of the time course of antibody-induced antigen mobility revealed a rapid and a delayed phase of redistribution. During the rapid phase (10 min or less) some of the antigen-bearing cells reorganized AAC into patches, while the remainder maintained a diffuse distribution. A fraction of the cells with either diffuse or patchy distribution also redistributed AAC into a pattern of ‘marginal redistribution (MR)’, consisting of linear aggreagation of AAC, at the cell edge. During the ‘late’ phase of redistribution (after about 20 min), AAC began to condense into one or more foci of coalescence (FC) on each cell. As the number of cells with FC increased with time, the fraction of cells which were labelled decreased. Electron-microscopic observation of thin sections of ferritin-labelled specimens indicated that AAC were lost by endocytosis and that this process was probably related to FC formation. Inhibitors of oxidative phosphorylation, protein synthesis, RNA synthesis, or microtubule assembly had no significant effect on the patterns or the course of redistribution. Iodoacetic acid (IAA), which depletes cellular ATP, and cytochalasin B (CB), which is believed to depolymerize microfilaments, partially inhibited MR and completely prevented FC formation and endocytosis. Paradoxically, IAA or CB-treated cells lost AAC very rapidly by some alternate mechanism not involving FC formation but which may entail a centrifugal migration of complexes to the cell extremities during the process of AAC disposal.

scholarly journals Perioperative metabolic acidosis: The Bradford Anaesthetic Department Acidosis Study

2018 ◽  
Vol 20 (1) ◽  
pp. 11-17 ◽  
Author(s):  
TO Lawton ◽  
A Quinn ◽  
SJ Fletcher
Keyword(s):  
Intensive Care Unit ◽  
Intensive Care ◽  
Metabolic Acidosis ◽  
Early Phase ◽  
Time Course ◽  
Late Phase ◽  
Common Finding ◽  
Major Surgery ◽  
Arterial Blood ◽  
Early Fluid

Metabolic acidosis is considered deleterious but is common in post-surgical patients admitted to intensive care unit. We evaluated the prevalence and time course of metabolic acidosis in elective major surgery, and generated hypotheses about causes, by hourly arterial blood sampling in 92 patients. Metabolic acidosis began before incision and most had occurred by the next hour. Seventy-eight per cent of patients had a significant metabolic acidosis post-operatively. Two overlapping phases were observed. The early phase started before incision, characterised by a rising chloride and falling anion gap, unrelated to saline use. The late phase was partly associated with lactate, related to surgery type, and early fluids appeared protective. There was a trend towards longer intensive care unit (+1.3 days) and hospital (+3.2 days) stay with metabolic acidosis. This is the first large study of the evolution of this common finding, demonstrating a pre-incision component. The early phase appears unavoidable or unpredictable, but the late phase might be modified by early fluid administration. It remains unclear whether acidosis of this type should be avoided.

scholarly journals Computation Tomography (CT)-Based Evaluation of Temporal Changes in Lung Abnormalities During the Recovery Stage in COVID-19 In-Hospital Patients

2021 ◽  
Author(s):  
Yanjing Wang ◽  
Robert Lakin ◽  
Nan Jiang ◽  
Bo Yang ◽  
Daoyuan Si ◽  
...  
Keyword(s):  
Clinical Characteristics ◽  
Time Course ◽  
Late Phase ◽  
Area Under The Curve ◽  
Temporal Changes ◽  
Lung Lesion ◽  
Initial Symptom ◽  
Time Curve ◽  
Lung Abnormalities ◽  
D Dimer

Abstract Objectives: To assess the late phase CT changes of COVID-19 patients, and figure out factors predicting lung abnormality in late phase.Methods: We conducted a retrospective study on 42 patients (14 males, 28 females; age 65±10 years) with COVID-19 admitted between February 7, 2020 and March 27, 2020. Only patients with at least 3 CT scans taken at least 3 weeks after initial symptom onset were included in the study. CT images were analyzed by 2 independent radiologists using different scoring: (1) area-based scoring (ABS); and (2) intensity-weighted scoring (IWS). Temporal changes in the average lung lesion were evaluated by averaged area under the curve (AUC) of the CT score-time curve. Correlations between averaged AUCs and clinical characteristics were determined. Results: Temporal changes in lung abnormalities during recovery (weeks 3 through 8) of CT findings using the ABS system were variable (P=0.934). By contrast, the IWS system detected more subtle changes in lung abnormalities during the late phase of recovery in COVID-19 patients, with consistent week-to-week relative reductions in IWS (P=0.025). In assessing the correlation between averaged AUCs and clinical characteristics, strong relationships were observed with D-dimer and C-reactive protein (CRP) levels on admission, with hazard ratios (HR)(95%CI) of 5.32 (1.25-22.6)(P=0.026) and 1.05 (1.10-1.09)(P=0.017), respectively. Conclusion: Our results suggest an intensity-weighted rather than area-based scoring system is more sensitive to detect subtle temporal CT changes in COVID-19, with D-dimer and CRP levels on admission being predictive of the time course of late phase recovery from the disease.

Enhancement of glucose transport in response to inhibition of oxidative metabolism: pre- and posttranslational mechanisms

1992 ◽  
Vol 262 (2) ◽  
pp. C527-C532 ◽  
Author(s):  
M. Shetty ◽  
J. N. Loeb ◽  
F. Ismail-Beigi
Keyword(s):  
Glucose Transport ◽  
Time Course ◽  
External Medium ◽  
Late Phase ◽  
Standard Medium ◽  
Glut 1 ◽  
Mrna Content ◽  
Glycogen Stores ◽  
Intracellular Glucose ◽  
Stimulation Of

Addition of 5 mM sodium azide to Clone 9 cells, a rat liver cell line characterized by intracellular glucose concentrations of less than 10% that of the external medium and limited glycogen stores, results in a 50-80% reduction in cell ATP content within 20 min which then recovers to near-basal levels within 1 h and is subsequently maintained at normal levels for 24 h despite continuing the presence of the inhibitor. Associated with this adaptive response is a striking stimulation of facilitated glucose transport, mediated by the GLUT-1 transporter, that exhibits "early" and "late" phases that appear to be mechanistically different. During the early phase of the response (0-2 h), glucose transport rate is enhanced 12-fold in the absence of any change in cell GLUT-1 or GLUT-1 mRNA content. In contrast, the late phase of the response (8-24 h) is characterized by a further large stimulation of glucose transport (to 1.6 times the 2-h value) that is associated with 2- to 3- and 6- to 10-fold increments in cell GLUT-1 and GLUT-1 mRNA content, respectively. In time course studies an increase in GLUT-1 mRNA content was observed at 4 h and preceded the increment in GLUT-1 which became detectable after 8 h of exposure to azide. A marked induction of GLUT-1 mRNA by azide was also demonstrable in cells incubated in medium containing higher concentrations of glucose (10.6 mM), although the increment was approximately 20% less than when cells were incubated in standard medium (containing 5.6 mM glucose).(ABSTRACT TRUNCATED AT 250 WORDS)

The Immunocompromised Patient: Non-AIDS

Chest Imaging ◽  
2019 ◽  
pp. 245-250
Author(s):  
Juliana Bueno
Keyword(s):  
Time Course ◽  
Opportunistic Infections ◽  
Late Phase ◽  
Organ Transplant ◽  
Marrow Transplant ◽  
Solid Organ ◽  
Heterogenous Group ◽  
Normal Chest Radiograph ◽  
Normal Chest ◽  
Chronic Corticosteroid

Immunosuppression may be primary (i.e. congenital) or secondary (i.e acquired). Because immunodeficiencies constitute an extensive and highly heterogenous group of diseases, imaging interpretation must be performed in light of the underlying condition and/or treatment timeline whenever possible. Secondary immunodeficiencies include those occurring in bone marrow transplant (BMT) and solid organ transplant recipients and in patients on chronic corticosteroid therapy. Familiarity with the time course of immune dysfunction following BMT is essential for providing a narrow differential diagnosis in cases of opportunistic infection. Opportunistic infections in BMT recipients can be categorized based on the post-transplant phase: Neutropenic phase (<30 days, before engraftment); Early phase (30-100 days, after engraftment); Late phase (>100 days). A normal chest radiograph does not exclude infection in immunocompromissed patients with respiratory symptoms; further assessment with chest CT should always be considered in order to detect subtle imaging abnormalities. Infectious bronchiolitis manifesting with centrilobular nodules and diffuse ground-glass opacities on CT is commonly seen in immunocompromised patients.

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