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Journal articleCoates MS, Alton EWFW, Brookes DW, et al., 2016,
INCREASED RESPIRATORY SYNCYTIAL VIRUS BURDEN LEADS TO MORE RAPID CELL DEATH IN PHE508DEL BRONCHIAL EPITHELIAL CELLS
, THORAX, Vol: 71, Pages: A44-A44, ISSN: 0040-6376 -
Conference paperGunawardana 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 -
Journal articleAlton EW, Beekman JM, Boyd AC, et al., 2016,
Preparation for a first-in-man lentivirus trial in patients with cystic fibrosis
, Thorax, Vol: 72, Pages: 137-147, ISSN: 0040-6376We have recently shown that non-viral gene therapy can stabilise the decline of lung function in patients with cystic fibrosis (CF). However, the effect was modest, and more potent gene transfer agents are still required. Fuson protein (F)/Hemagglutinin/Neuraminidase protein (HN)-pseudotyped lentiviral vectors are more efficient for lung gene transfer than non-viral vectors in preclinical models. In preparation for a first-in-man CF trial using the lentiviral vector, we have undertaken key translational preclinical studies. Regulatory-compliant vectors carrying a range of promoter/enhancer elements were assessed in mice and human air-liquid interface (ALI) cultures to select the lead candidate; cystic fibrosis transmembrane conductance receptor (CFTR) expression and function were assessed in CF models using this lead candidate vector. Toxicity was assessed and 'benchmarked' against the leading non-viral formulation recently used in a Phase IIb clinical trial. Integration site profiles were mapped and transduction efficiency determined to inform clinical trial dose-ranging. The impact of pre-existing and acquired immunity against the vector and vector stability in several clinically relevant delivery devices was assessed. A hybrid promoter hybrid cytosine guanine dinucleotide (CpG)- free CMV enhancer/elongation factor 1 alpha promoter (hCEF) consisting of the elongation factor 1α promoter and the cytomegalovirus enhancer was most efficacious in both murine lungs and human ALI cultures (both at least 2-log orders above background). The efficacy (at least 14% of airway cells transduced), toxicity and integration site profile supports further progression towards clinical trial and pre-existing and acquired immune responses do not interfere with vector efficacy. The lead rSIV.F/HN candidate expresses functional CFTR and the vector retains 90-100% transduction efficiency in clinically relevant delivery devices. The data support the progression of the F/HN-pseudotype
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Journal articleAbbara 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 -
Journal articleAbbara 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 -
Conference paperJha 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: 0903-1936Background: 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.
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Journal articleSchuijs MJ, Hartmann S, Selkirk ME, et al., 2016,
The Helminth-Derived Immunomodulator AvCystatin Reduces Virus Enhanced Inflammation by Induction of Regulatory IL-10+ T Cells.
, PLOS One, Vol: 11, ISSN: 1932-6203Respiratory Syncytial Virus (RSV) is a major pathogen causing low respiratory tract disease (bronchiolitis), primarily in infants. Helminthic infections may alter host immune responses to both helminths and to unrelated immune triggers. For example, we have previously shown that filarial cystatin (AvCystatin/Av17) ameliorates allergic airway inflammation. However, helminthic immunomodulators have so far not been tested in virus-induced disease. We now report that AvCystatin prevents Th2-based immunopathology in vaccine-enhanced RSV lung inflammation, a murine model for bronchiolitis. AvCystatin ablated eosinophil influx, reducing both weight loss and neutrophil recruitment without impairing anti-viral immune responses. AvCystatin also protected mice from excessive inflammation following primary RSV infection, significantly reducing neutrophil influx and cytokine production in the airways. Interestingly, we found that AvCystatin induced an influx of CD4+ FoxP3+ interleukin-10-producing T cells in the airway and lungs, correlating with immunoprotection, and the corresponding cells could also be induced by adoptive transfer of AvCystatin-primed F4/80+ macrophages. Thus, AvCystatin ameliorates enhanced RSV pathology without increasing susceptibility to, or persistence of, viral infection and warrants further investigation as a possible therapy for virus-induced airway disease.
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Journal articleMakris S, Bajorek M, Culley F, et al., 2016,
Alveolar Macrophages Can Control Respiratory Syncytial Virus Infection in the Absence of Type I Interferons
, Journal of Innate Immunity, Vol: 8, ISSN: 1662-8128 -
Journal articleAlton E, Griesenbach U, Davies JC, et al., 2015,
A randomised, double-blind, placebo-controlled trial of repeated nebulisation of non-viral CFTR gene therapy in patients with cystic fibrosis
, Lancet Respiratory Medicine, ISSN: 2213-2619 -
Journal articleHabibi MS, Jozwik A, Makris S, et al., 2015,
Impaired antibody-mediated protection and defective IgA B cell memory in experimental infection of adults with respiratory syncytial virus
, American Journal of Respiratory and Critical Care Medicine, Vol: 191, ISSN: 1535-4970Rationale: Despite relative antigenic stability, respiratory syncytial virus (RSV) re-infects throughout life. After >40 years of research, no effective human vaccine exists and correlates of protection remain poorly defined. Most current vaccine candidates seek to induce high levels of RSV-specific serum neutralizing antibodies, which are associated with reduced RSV-related hospitalization rates in observational studies but may not actually prevent infection. Objectives: Characterize correlates of protection from infection and the generation of RSV-specific humoral memory to promote effective vaccine development. Methods: We inoculated 61 healthy adults with live RSV and studied protection from infection by serum and mucosal antibody. We analyzed RSV-specific peripheral blood plasmablast and memory B cell frequencies and antibody longevity. Measurements and Main Results: Despite moderately high levels of pre-existing serum antibody, 34 (56%) became infected, of whom 23 (68%) developed symptomatic colds. Prior RSV-specific nasal IgA correlated significantly more strongly with protection from PCR-confirmed infection than serum neutralizing antibody. Increases in virus-specific antibody titers were variable and transient in infected subjects, but correlated with plasmablasts that peaked around day 10. During convalescence, only IgG (and no IgA) RSV-specific memory B cells were detectable in peripheral blood. This contrasted with natural influenza infection, where virus-specific IgA memory B cells were readily recovered. Conclusions: This observed specific defect in IgA memory may partly explain RSV's ability to cause recurrent symptomatic infections. If so, vaccines able to induce durable RSV-specific IgA responses may be more protective than those generating systemic antibody alone.
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