140 results found
Progatzky F, Jha A, Wane M, et al., 2019, Induction of innate cytokine responses by respiratory mucosal challenge with R848 in zebrafish, mice and humans, Journal of Allergy and Clinical Immunology, ISSN: 0091-6749
We compared live zebrafish, mouse and human nasal challenge responses to the TLR7/8 agonist resiquimod (R848). We found remarkably similar induction of mediators in the three species, offering novel mucosal models of innate anti-viral immunity.
Dunning J, Blankley S, Hoang LT, et al., 2019, Author Correction: Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza., Nature Immunology, Vol: 20, Pages: 373-373, ISSN: 1529-2908
In the version of this article initially published, a source of funding was not included in the Acknowledgements section. That section should include the following: P.J.M.O. was supported by EU FP7 PREPARE project 602525. The error has been corrected in the HTML and PDF version of the article.
Spadaro S, Park M, Turrini C, et al., 2019, Biomarkers for Acute Respiratory Distress syndrome and prospects for personalised medicine, Journal of Inflammation, Vol: 16, ISSN: 1476-9255
Acute lung injury (ALI) affects over 10% of patients hospitalised in critical care, with acute respiratory distress syndrome (ARDS) being the most severe form of ALI and having a mortality rate in the region of 40%. There has been slow but incremental progress in identification of biomarkers that contribute to the pathophysiology of ARDS, have utility in diagnosis and monitoring, and that are potential therapeutic targets (Calfee CS, Delucchi K, Parsons PE, Thompson BT, Ware LB, Matthay MA, Thompson T, Ware LB, Matthay MA, Lancet Respir Med 2014, 2:611–-620). However, a major issue is that ARDS is such a heterogeneous, multi-factorial, end-stage condition that the strategies for “lumping and splitting” are critical (Prescott HC, Calfee CS, Thompson BT, Angus DC, Liu VX, Am J Respir Crit Care Med 2016, 194:147–-155). Nevertheless, sequencing of the human genome, the availability of improved methods for analysis of transcription to mRNA (gene expression), and development of sensitive immunoassays has allowed the application of network biology to ARDS, with these biomarkers offering potential for personalised or precision medicine (Sweeney TE, Khatri P, Toward precision medicine Crit Care Med; 2017 45:934-939).Biomarker panels have potential applications in molecular phenotyping for identifying patients at risk of developing ARDS, diagnosis of ARDS, risk stratification and monitoring. Two subphenotypes of ARDS have been identified on the basis of blood biomarkers: hypo-inflammatory and hyper-inflammatory. The hyper-inflammatory subphenotype is associated with shock, metabolic acidosis and worst clinical outcomes. Biomarkers of particular interest have included interleukins (IL-6 and IL-8), interferon gamma (IFN-γ), surfactant proteins (SPD and SPB), von Willebrand factor antigen, angiopoietin 1/2 and plasminogen activator inhibitor-1 (PAI-1). In terms of gene expression (mRNA) in blood there have been found to be increases in neutrophil-re
Tavares J, Tunstall T, Pizzichini M, et al., 2018, IL-5 levels in nasosorption and sputosorption correlate with sputum eosinophilia in allergic asthma, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
Swieboda D, Thwaites R, Nadel S, et al., 2018, The role of innate lymphoid cells in early life lung infection, 28th International Congress of the European-Respiratory-Society (ERS), Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Dunning J, Blankley S, Hoang LT, et al., 2018, Progression of whole-blood transcriptional signatures from interferon-induced to neutrophil-associated patterns in severe influenza, Nature Immunology, ISSN: 1529-2916
Transcriptional profiles and host-response biomarkers are used increasingly to investigate the severity, subtype and pathogenesis of disease. We now describe whole-blood mRNA signatures and concentrations of local and systemic immunological mediators in 131 adults hospitalized with influenza, from whom extensive clinical and investigational data were obtained by MOSAIC investigators. Signatures reflective of interferon-related antiviral pathways were common up to day 4 of symptoms in patients who did not require mechanical ventilator support; in those who needed mechanical ventilation, an inflammatory, activated-neutrophil and cell-stress or death (‘bacterial’) pattern was seen, even early in disease. Identifiable bacterial co-infection was not necessary for this ‘bacterial’ signature but was able to enhance its development while attenuating the early ‘viral’ signature. Our findings emphasize the importance of timing and severity in the interpretation of host responses to acute viral infection and identify specific patterns of immune-system activation that might enable the development of novel diagnostic and therapeutic tools for severe influenza.
Thwaites RS, Gunawardana NC, Broich V, et al., 2018, Biphasic activation of complement and fibrinolysis during the human nasal allergic response, Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 1892-1895.e6, ISSN: 0091-6749
Complement, coagulation and fibrinolysis contribute to the pathology of many respiratory diseases. Here we detail the biphasic activation of these pathways following nasal allergen challenge. Understanding these mechanisms may lead to therapeutic insight in common respiratory diseases.
Thwaites RS, Coates M, Ito K, et al., 2018, Reduced nasal viral load and IFN responses in infants with RSV bronchiolitis and respiratory failure, American Journal of Respiratory and Critical Care Medicine, ISSN: 1073-449X
RATIONALE: Respiratory syncytial virus (RSV) bronchiolitis is a major cause of morbidity and mortality in infancy. Severe disease is thought to result from uncontrolled viral replication, an excessive immune response, or both. OBJECTIVES: To determine RSV load and immune mediator levels in nasal mucosal lining fluid by serial sampling of nasal fluids from cases of moderate and severe bronchiolitis over the course of infection. METHODS: Infants with viral bronchiolitis necessitating admission (n=55) were recruited from a paediatric centre during 2016/17. Of these, 30 were RSV infected (18 'moderate', and 12 mechanically ventilated 'severe'). Nasal fluids were sampled frequently over time using nasosorption devices and nasophayngeal aspiration (NPA). Hierarchical clustering of time weighted averages (TWA) was performed to investigate cytokine and chemokine levels, and gene expression profiling was conducted. MEASUREMENTS AND MAIN RESULTS: Unexpectedly, cases of severe RSV bronchiolitis had lower nasal viral loads and reduced interferon (IFN)-γ and CCL5/RANTES levels compared to those with moderate disease, especially when allowance was made for disease duration (all P<0.05). Reduced cytokine/chemokine levels in severe disease were also seen in children with other viral infections. Gene expression analysis of NPA samples (n=43) confirmed reduced type-I IFN gene expression in severe bronchiolitis accompanied by enhanced expression of MUC5AC and IL17A. CONCLUSIONS: Infants with severe RSV bronchiolitis have lower nasal viral load, IP-10/CXCL10 and type-I IFNs levels compared to moderately ill children, but enhanced MUC5AC and IL17A gene expression in nasal cells.
Cai F, Abreu F, Ding HT, et al., 2018, Nasal Biomarkers Characterization In Lebrikizumab Bronchoscopy Study (CLAVIER), American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB118-AB118, ISSN: 0091-6749
Dhariwal J, Cameron A, Wong E, et al., 2018, Pulmonary Innate Lymphoid Cell Responses During Rhinovirus-Induced Asthma Exacerbations, American-Academy-of-Allergy-Asthma-and-Immunology / World-Allergy-Organization Joint Congress, Publisher: MOSBY-ELSEVIER, Pages: AB195-AB195, ISSN: 0091-6749
Thwaites RS, Jarvis HC, Singh N, et al., 2018, Absorption of nasal and bronchial fluids: precision sampling of the human respiratory mucosa and laboratory processing of samples, Jove-Journal of Visualized Experiments, Vol: 131, ISSN: 1940-087X
The methods of nasal absorption (NA) and bronchial absorption (BA) use synthetic absorptive matrices (SAM) to absorb the mucosal lining fluid (MLF) of the human respiratory tract. NA is a non-invasive technique which absorbs fluid from the inferior turbinate, and causes minimal discomfort. NA has yielded reproducible results with the ability to frequently repeat sampling of the upper airway. By comparison, alternative methods of sampling the respiratory mucosa, such as nasopharyngeal aspiration (NPA) and conventional swabbing, are more invasive and may result in greater data variability. Other methods have limitations, for instance, biopsies and bronchial procedures are invasive, sputum contains many dead and dying cells and requires liquefaction, exhaled breath condensate (EBC) contains water and saliva, and lavage samples are dilute and variable. BA can be performed through the working channel of a bronchoscope in clinic. Sampling is well tolerated and can be conducted at multiple sites in the airway. BA results in MLF samples being less dilute than bronchoalveolar lavage (BAL) samples. This article demonstrates the techniques of NA and BA, as well as the laboratory processing of the resulting samples, which can be tailored to the desired downstream biomarker being measured. These absorption techniques are useful alternatives to the conventional sampling techniques used in clinical respiratory research.
Jha A, Thwaites RS, Tunstall T, et al., 2018, Human Nasal Challenge with TLR7/8 Agonist Resiquimod (R848) Induces Mucosal Interferon-alpha, with Increased Responsiveness in Asthmatic Volunteers, International Conference of the American-Thoracic-Society, Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Jarvis H, Thwaites R, Tunstall T, et al., 2017, Isolated mediastinal lymph node tuberculosis (IMLNTB) is characterised by elevation in systemic and bronchial IL-12 pathway mediators compared to pulmonary TB
Gunawardana NC, Zhao Q, Carayannopoulos LN, et al., 2017, The effects of house dust mite sublingual immunotherapy tablet on immunologic biomarkers and nasal allergen challenge symptoms., Journal of Allergy and Clinical Immunology, Vol: 141, Pages: 785-788.e9, ISSN: 0091-6749
Tunstall T, Kon OM, Bartlett N, et al., 2017, A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13), EBioMedicine, Vol: 19, Pages: 128-138, ISSN: 2352-3964
BackgroundRhinovirus infection is a major cause of asthma exacerbations.ObjectivesWe studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations.MethodsWe used nasosorption on days 0, 2–5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n = 28) and healthy non-atopic controls (n = 11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay.ResultsFollowing rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P < 0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0–7, all P < 0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P < 0.01) and levels increased by days 3 and 4 (P < 0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7 days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P < 0.05).ConclusionsPrecision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation.
Thwaites RS, Ito K, Chingono JMS, et al., 2017, Nasosorption is a minimally invasive diagnostic procedure for measurement of viral load and markers of mucosal inflammation in RSV bronchiolitis, The Journal of Infectious Diseases, Vol: 215, Pages: 1240-1244, ISSN: 1537-6613
Background.Existing respiratory mucosal sampling methods are flawed, particularly in a pediatric bronchiolitis setting.Methods.Twenty-four infants with bronchiolitis were recruited: 12 were respiratory syncytial virus (RSV)–positive, 12 were RSV-negative. Infants were sampled by nasosorption and nasopharyngeal aspiration (NPA).Results.Nasosorption was well tolerated and identified all RSV+ samples. RSV load measured by nasosorption (but not NPA) correlated with length of hospital stay (P = .04) and requirement for mechanical ventilation (P = .03). Nasosorption (but not NPA) levels of interferon γ, interleukin 1β, CCL5/RANTES, and interleukin 10 (IL-10) were elevated in RSV+ bronchiolitis (all P < .05), furthermore CCL5 and IL-10 correlated with RSV load (P < .05).Conclusions.Nasosorption allowed measurement of RSV load and the mucosal inflammatory response in infants.
Thwaites RS, Gunawardana NC, Broich VL, et al., 2017, Activation of the complement, coagulation and fibrinolysis pathways after nasal allergen challenge, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: Elsevier, Pages: AB384-AB384, ISSN: 0091-6749
Gunawardana NC, Jain A, Zhao Q, et al., 2017, Biomarkers of 12 SQ House Dust Mite Sublingual Immunotherapy (SLIT)-Tablet Treatment After Nasal Allergen Challenge, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB192-AB192, ISSN: 0091-6749
Dhariwal J, Cameron A, Trujillo-Torralbo MB, et al., 2017, Mucosal type 2 innate lymphoid cells are a key component of the allergic response to aeroallergen, American Journal of Respiratory and Critical Care Medicine, Vol: 195, Pages: 1586-1596, ISSN: 1535-4970
RATIONALE: Newly characterised type 2 innate lymphoid cells display potent type 2 effector functionality, however their contribution to allergic airways inflammation and asthma is poorly understood. Mucosal biopsy used to characterise the airway mucosa is invasive, poorly tolerated and does not allow sequential sampling. OBJECTIVES: To assess the role of type 2 innate lymphoid cells during nasal allergen challenge in subjects with allergic rhinitis, using novel non-invasive methodology. METHODS: We used a human experimental allergen challenge model, with flow cytometric analysis of nasal curettage samples, to assess the recruitment of type 2 innate lymphoid cells and granulocytes to the upper airways of atopic and healthy subjects following allergen provocation. Soluble mediators in the nasal lining fluid were measured using nasosorption. MEASUREMENTS AND MAIN RESULTS: Following allergen challenge, atopic subjects displayed rapid induction of upper airway symptoms, an enrichment of type 2 innate lymphoid cells, eosinophils and neutrophils, along with increased production of interleukin-5, prostaglandin D2, and eosinophil and T-helper type 2 cell chemokines compared to healthy subjects. The most pronounced type 2 innate lymphoid cell recruitment was observed in patients with elevated serum IgE and airway eosinophilia. CONCLUSIONS: The rapid recruitment of type 2 innate lymphoid cells to the upper airways of allergic rhinitis patients, and their association with key type 2 mediators, highlights their likely important role in the early allergic response to aeroallergen in the airways. The novel methodology described herein enables the analysis of rare cell populations from non-invasive, serial tissue sampling.
Pruski P, MacIntyre DA, Lewis HV, et al., 2016, Medical swab analysis using desorption electrospray ionization mass spectrometry (DESI-MS) – a non-invasive approach for mucosal diagnostics, Analytical Chemistry, Vol: 89, Pages: 1540-1550, ISSN: 0003-2700
Medical swabs are routinely used worldwide to sample human mucosa for microbiological screening with culture methods. These are usually time-consuming and have a narrow focus on screening for particular microorganism species. As an alternative, direct mass spectrometric profiling of the mucosal metabolome provides a broader window into the mucosal ecosystem. We present for the first time a minimal effort/minimal-disruption technique for augmenting the information obtained from clinical swab analysis with mucosal metabolome profiling using desorption electrospray ionization mass spectrometry (DESI-MS) analysis. Ionization of mucosal biomass occurs directly from a standard rayon swab mounted on a rotating device and analyzed by DESI MS using an optimized protocol considering swab–inlet geometry, tip–sample angles and distances, rotation speeds, and reproducibility. Multivariate modeling of mass spectral fingerprints obtained in this way readily discriminate between different mucosal surfaces and display the ability to characterize biochemical alterations induced by pregnancy and bacterial vaginosis (BV). The method was also applied directly to bacterial biomass to confirm the ability to detect intact bacterial species from a swab. These results highlight the potential of direct swab analysis by DESI-MS for a wide range of clinical applications including rapid mucosal diagnostics for microbiology, immune responses, and biochemistry.
Gunawardana N, Campbell G, Lindsley S, et al., 2016, The effect of vitamin D supplementation on cathelicidin levels, vitamin D receptor (VDR) and E-cadherin expression after nasal allergen challenge in allergic rhinitis, Annual Meeting of the British-Society-for-Allergy-and-Clinical-Immunology (BSACI), Publisher: WILEY-BLACKWELL, Pages: 1666-1666, ISSN: 0954-7894
Abbara A, Mahomed Z, Collin SM, et al., 2016, OLDER PATIENTS WITH TUBERCULOSIS HAVE LESS TYPICAL CHANGES ON CHEST RADIOGRAPHS, THORAX, Vol: 71, Pages: A143-A143, ISSN: 0040-6376
Abbara A, Hardman E, Collin SM, et al., 2016, THE NATURE AND DURATION OF SYMPTOMS AND TIME TO STARTING TREATMENT COMPARING OLDER WITH YOUNGER PULMONARY TUBERCULOSIS PATIENTS, THORAX, Vol: 71, Pages: A51-A52, ISSN: 0040-6376
Jha A, Dunning J, Tunstall T, et al., 2016, Asthma patients hospitalized with influenza lack mucosal and systemic type 2 inflammation, European Respiratory Society Congress, Publisher: European Respiratory Society, ISSN: 0903-1936
Background: Asthmatic persons tend to suffer from severe influenza, but the reasons for enhanced severity are unknown. Objectives: To determine the clinicopathological correlates of this susceptibility, we examined nasal and systemic immune responses in adults admitted to hospital with influenza-like illnesses. Methods: We studied 210 patients admitted with influenza-like illness at 11 hospitals in the UK across 2 winter seasons (2009/10 and 2010/11). Of these, 133 (63%) had confirmed influenza and 40/133 (30%) were asthmatic. We measured a panel of cytokines and chemokines in serum and nasal mucosal lining fluid and compared results in asthmatics, non-asthmatics and healthy control volunteers. Results: Asthma patients were more often female than non-asthmatics (70% vs 39% respectively), required less mechanical ventilation (15% vs 37.6%) and had shorter hospital stays (mean 8.3 vs 15.3 days, all P <0.05). Despite having equivalent nasopharyngeal influenza viral load, asthmatics had higher serum IFN-α levels but lower serum TNF-α, IL-5, IL-6 and CXCL8 (all P<0.05). In the nasal mucosa, asthmatics and non-asthmatics had comparable levels of soluble mediators. In particular, asthmatics showed no evidence of increased type 2 inflammation (IL-5 and IL-13) or deficient interferon responses. Conclusions: Adult asthmatics hospitalised with influenza show a propensity to be female with markedly reduced morbidity and systemic inflammation than non-asthmatics. Against expectation, asthmatics did not have increased type 2 inflammation. This study highlights the importance of defining underlying immune responses to infection in individual patients to enable future delivery of personalized therapy.
Minshall E, Patel H, Francis N, et al., 2016, Local chemokine profiling in eosinophilic esophagitis: the Synthetic Absorptive Matrix test, Pediatric Allergy and Immunology, Vol: 28, Pages: 100-102, ISSN: 1399-3038
We describe a novel method of sampling the esophageal lining fluid in children and show that levels of eotaxin-1 and MCP-4 differentiate those children with a histological diagnosis of EoE from those without. This article is protected by copyright. All rights reserved.
Leaker BR, Malkov VA, Mogg R, et al., 2016, The nasal mucosal late allergic reaction to grass pollen involves type 2 inflammation (IL-5 and IL-13), the inflammasome (IL-1β), and complement, Mucosal Immunology, Vol: 10, Pages: 408-420, ISSN: 1935-3456
Non-invasive mucosal sampling (nasosorption and nasal curettage) was used following nasal allergen challenge with grass pollen in subjects with allergic rhinitis, in order to define the molecular basis of the late allergic reaction (LAR). It was found that the nasal LAR to grass pollen involves parallel changes in pathways of type 2 inflammation (IL-4, IL-5 and IL-13), inflammasome-related (IL-1β), and complement and circadian-associated genes. A grass pollen nasal spray was given to subjects with hay fever followed by serial sampling, in which cytokines and chemokines were measured in absorbed nasal mucosal lining fluid, and global gene expression (transcriptomics) assessed in nasal mucosal curettage samples. Twelve of 19 subjects responded with elevations in interleukin (IL)-5, IL-13, IL-1β and MIP-1β/CCL4 protein levels in the late phase. In addition, in these individuals whole-genome expression profiling showed upregulation of type 2 inflammation involving eosinophils and IL-4, IL-5 and IL-13; neutrophil recruitment with IL-1α and IL-1β; the alternative pathway of complement (factor P and C5aR); and prominent effects on circadian-associated transcription regulators. Baseline IL-33 mRNA strongly correlated with these late-phase responses, whereas a single oral dose of prednisone dose-dependently reversed most nasal allergen challenge-induced cytokine and transcript responses. This study shows that the LAR to grass pollen involves a range of inflammatory pathways and suggests potential new biomarkers and therapeutic targets. Furthermore, the marked variation in mucosal inflammatory events between different patients suggests that in the future precision mucosal sampling may enable rational specific therapy.
Batista C, McIntosh M, Hansel T, et al., 2016, Elevated concentrations of CXCL8 in the nasal mucosal lining fluid of COPD patients as an accessible surrogate measure of bronchial levels, Publisher: EUROPEAN RESPIRATORY SOC JOURNALS LTD, ISSN: 0903-1936
Poletti D, Iannini V, Casolari P, et al., 2016, Nasal inflammation and its response to local glucocorticoid regular treatment in patients with persistent non-allergic rhinitis: a pilot study, Journal of Inflammation, Vol: 13, ISSN: 1476-9255
Background The pathogenesis of non-allergic rhinitis (NAR) is still largely unknown. Furthermore, it is unclear whether there is a correlation between the effect of nasal glucocorticoids on nasal inflammation and on nasal symptoms and quality of life. Methods In this pilot study we recruited 12 healthy subjects and 24 patients with recently diagnosed persistent NAR [12 untreated and 12 under regular treatment with nasal fluticasone furoate (two sprays of 27.5 µg each in each nostril once daily, total daily dose=110 µg) for at least 20 days]. Each subject filled a mini rhinoconjunctivitis quality of life questionnaire (mini RQLQ). Nasal scrapings were obtained from each subject and used to prepare slides for Diff-Quik and immunocytochemical staining for inflammatory and epithelial cells count, MUC5AC expression and the general pro-inflammatory transcription factor nuclear factor B (NF-B) activation. Results The nasal score of the mini RQLQ, the number of nasal inflammatory cells (neutrophils, eosinophils) and the number of goblet cells are significantly higher in untreated patients with persistent NAR compared with control subjects and treated NAR patients. The percentage of MUC5AC+ nasal epithelial cells is significantly increased in untreated patients with persistent NAR compared with the control subjects (41.8±6.4 vs 22.3±4.8, respectively; p=0.0403) without significant differences between control subjects and patients with persistent NAR on regular fluticasone furoate treatment with nasal glucocorticoids (33.9±5.0%; p=0.0604) nor between the 2 groups of persistent NAR subjects (p=0.3260). The number of cytosolic and/or nuclear p65+ nasal epithelial and inflammatory cells was not significantly different between the three groups. Conclusions Patients with persistent untreated NAR, compared with normal control subjects and patients with persistent NAR under regular treatment with nasal fluticasone furoate glucocorticoids by at lea
Jha A, Progatzky F, Wane M, et al., 2016, Human nasal mucosal responses to TLR agonists are mirrored by the zebrafish gill, British Association of Lung Research Summer Congress
Introduction: There are few reliable ways to study respiratory mucosal immune responses to viruses, viral-type toll-like receptor (TLR) agonists and vaccines. To investigate innate immune responses to TLR agonists (TLR3: poly IC/ poly ICLC; TLR7/8: resiquimod), we compared the effects on human nasal mucosa and zebrafish gills in vivo. Methods: Nasal challenge of adult volunteers was performed with saline, poly IC (n=4), poly ICLC (n=4) or resiquimod (n=8; 5 non-atopic, 3 atopic). Nasal mucosal lining fluid (MLF) was obtained by nasosorption at regular intervals up to 24 hours after challenge; nasal obstruction was monitored by peak nasal inspiratory flow (PNIF) and total nasal symptom scores (TNSS). Cytokines and interferons were measured in MLF using electrochemiluminescence on the Meso Scale Discovery (MSD) platform. Adult zebrafish gills were exposed to the same TLR agonists and gene expression was quantified in gill tissue at similar time-points. Results: Nasal challenge with TLR3 agonists failed to elicit any significant responses when compared to saline. In contrast resiquimod (10μg/100μl per nostril) caused a potent induction of cytokines with an early release (1-3 hours) of IFN-α2a, TNF-α and IL-1β and a later release (after 4 hours) of IFN-γ. The 3 volunteers with the highest levels of IFN-α2a were atopic. Six volunteers were asymptomatic and two volunteers had flu-like symptoms. There were no significant changes in clinical correlates of nasal obstruction. After resiquimod administration, but not TLR3 agonists, zebrafish gills showed an immune profile remarkably analogous to human nasal responses. Conclusion: The TLR7/8 agonist resiquimod is a potent mucosal inducer of IFN-α2a, IFN-γ and proinflammatory cytokines, whilst TLR3 agonists failed to stimulate mucosal innate immune responses. Zebrafish gills accurately mimic human nasal mucosal responses following exposure to TLR agonists, offering translational app
Gunawardana NC, Campbell G, Lindsley S, et al., 2016, The Effect of Vitamin D Supplementation on Mucosal IL-5, MMP9 and Cathelicidin after Nasal Allergen Challenge with Grass Pollen, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB73-AB73, ISSN: 0091-6749
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