60 results found
Astrand A, Wingren C, Benjamin A, et al., 2017, Dapagliflozin-lowered blood glucose reduces respiratory Pseudomonas aeruginosa infection in diabetic mice, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 174, Pages: 836-847, ISSN: 0007-1188
Fischetti L, Zhong Z, Pinder CL, et al., 2017, The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling., Cytokine, Vol: 99, Pages: 287-296
Toll like receptor (TLR) ligands are important adjuvant candidates, causing antigen presenting cells to release inflammatory mediators, leading to the recruitment and activation of other leukocytes. The aim of this study was to define the response of human blood derived dendritic cells and macrophages to three TLR ligands acting singly or in combination, Poly I:C (TLR3), GLA (TLR4) and R848 (TLR7/8). Combinations of TLR agonists have been shown to have a synergistic effect on individual cytokines, here we look at the global inflammatory response measuring both cytokines and chemokines. Using a custom Luminex assay we saw dose responses in several mediators including CCL3 (MIP1α), IL-1α, IL-1β, IL-12, CXCL10 (IP-10) and IL-6, all of which were significantly increased by the combination of R848 and GLA, even when low dose GLA was added. The synergistic effect was inhibited by specific MAP kinase inhibitors blocking the kinases p38 and JNK but not MEK1. Combining TLR adjuvants also had a synergistic effect on cytokine responses in human mucosal tissue explants. From this we conclude that the combination of R848 and GLA potentiates the inflammatory profile of antigen presenting cells. Since the pattern of inflammatory mediators released can alter the quality and quantity of the adaptive immune response to vaccination, this study informs vaccine adjuvant design.
Gould VMW, Francis JN, Anderson KJ, et al., 2017, Nasal IgA provides protection against human influenza challenge in volunteers with low serum influenza antibody titre, Frontiers in Microbiology, Vol: 8, ISSN: 1664-302X
In spite of there being a number of vaccines, influenza remains a significant global cause of morbidity and mortality. Understanding more about natural and vaccine induced immune protection against influenza infection would help to develop better vaccines. Virus specific IgG is a known correlate of protection, but other factors may help to reduce viral load or disease severity, for example IgA. In the current study we measured influenza specific responses in a controlled human infection model using influenza A/California/2009 (H1N1) as the challenge agent. Volunteers were pre-selected with low haemagglutination inhibition (HAI) titres in order to ensure a higher proportion of infection; this allowed us to explore the role of other immune correlates. In spite of HAI being uniformly low, there were variable levels of H1N1 specific IgG and IgA prior to infection. There was also a range of disease severity in volunteers allowing us to compare whether differences in systemic and local H1N1 specific IgG and IgA prior to infection affected disease outcome. H1N1 specific IgG level before challenge did not correlate with protection, probably due to the pre-screening for individuals with low HAI. However, the length of time infectious virus was recovered from the nose was reduced in patients with higher pre-existing H1N1 influenza specific nasal IgA or serum IgA. Therefore, IgA contributes to protection against influenza and should be targeted in vaccines.
Kinnear E, Lambert L, McDonald JU, et al., 2017, Airway T cells protect against RSV infection in the absence of antibody, Mucosal Immunology, ISSN: 1933-0219
Tissue resident memory T (Trm) cells act as sentinels and early responders to infection. Respiratory syncytial virus (RSV)-specific Trm cells have been detected in the lungs after human RSV infection, but whether they have a protective role is unknown. To dissect the protective function of Trm cells, BALB/c mice were infected with RSV; infected mice developed antigen-specific CD8(+) Trm cells (CD103(+)/CD69(+)) in the lungs and airways. Intranasally transferring cells from the airways of previously infected animals to naïve animals reduced weight loss on infection in the recipient mice. Transfer of airway CD8 cells led to reduced disease and viral load and increased interferon-γ in the airways of recipient mice, while CD4 transfer reduced tumor necrosis factor-α in the airways. Because DNA vaccines induce a systemic T-cell response, we compared vaccination with infection for the effect of memory CD8 cells generated in different compartments. Intramuscular DNA immunization induced RSV-specific CD8 T cells, but they were immunopathogenic and not protective. Notably, there was a marked difference in the induction of Trm cells; infection but not immunization induced antigen-specific Trm cells in a range of tissues. These findings demonstrate a protective role for airway CD8 against RSV and support the need for vaccines to induce antigen-specific airway cells.Mucosal Immunology advance online publication, 24 May 2017; doi:10.1038/mi.2017.46.
Kinnear E, Lambert L, McDonald JU, et al., 2017, Airway T cells protect against RSV infection in the absence of antibody., Mucosal Immunol
This corrects the article DOI: 10.1038/mi.2017.46.
McDonald JU, Zhong Z, Groves HT, et al., 2017, Inflammatory responses to influenza vaccination at the extremes of age, IMMUNOLOGY, Vol: 151, Pages: 451-463, ISSN: 0019-2805
Tregoning J, 2017, No researcher is too junior to fix science, NATURE, Vol: 545, Pages: 7-7, ISSN: 0028-0836
de Silva TI, Gould V, Mohammed NI, et al., 2017, Comparison of mucosal lining fluid sampling methods and influenza-specific IgA detection assays for use in human studies of influenza immunity, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 449, Pages: 1-6, ISSN: 0022-1759
Badamchi-Zadeh A, McKay PF, Korber BT, et al., 2016, A Multi-Component Prime-Boost Vaccination Regimen with a Consensus MOMP Antigen Enghances Chlamydia trachomatis Clearance, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Gill SK, Hui K, Farne H, et al., 2016, Increased airway glucose increases airway bacterial load in hyperglycaemia, Scientific Reports, Vol: 6, ISSN: 2045-2322
Diabetes is associated with increased frequency of hospitalization due to bacterial lung infection.We hypothesize that increased airway glucose caused by hyperglycaemia leads to increasedbacterial loads. In critical care patients, we observed that respiratory tract bacterial colonisationis significantly more likely when blood glucose is high. We engineered mutants in genesaffecting glucose uptake and metabolism (oprB, gltK, gtrS and glk) in Pseudomonas aeruginosa,strain PAO1. These mutants displayed attenuated growth in minimal medium supplemented withglucose as the sole carbon source. The effect of glucose on growth in vivo was tested usingstreptozocin-induced, hyperglycaemic mice, which have significantly greater airway glucose.Bacterial burden in hyperglycaemic animals was greater than control animals when infected withwild type but not mutant PAO1. Metformin pre-treatment of hyperglycaemic animals reducedboth airway glucose and bacterial load. These data support airway glucose as a criticaldeterminant of increased bacterial load during diabetes.
Hewitt R, Webber J, Farne H, et al., 2016, Airway Glucose In Virus-Induced COPD Exacerbations, International Conference of the American-Thoracic-Society (ATS), Publisher: AMER THORACIC SOC, ISSN: 1073-449X
Lambert L, Kinnear E, McDonald JU, et al., 2016, DNA Vaccines Encoding Antigen Targeted to MHC Class II Induce Influenza-Specific CD8(+) T Cell Responses, Enabling Faster Resolution of Influenza Disease, FRONTIERS IN IMMUNOLOGY, Vol: 7, ISSN: 1664-3224
Mann JFS, Tregoning JS, Aldon Y, et al., 2016, CD71 targeting boosts immunogenicity of sublingually delivered influenza haemagglutinin antigen and protects against viral challenge in mice, JOURNAL OF CONTROLLED RELEASE, Vol: 232, Pages: 75-82, ISSN: 0168-3659
McDonald JU, Ekeruche-Makinde J, Ho MM, et al., 2016, Development of a custom pentaplex sandwich immunoassay using Protein-G coupled beads for the Luminex (R) xMAP (R) platform, JOURNAL OF IMMUNOLOGICAL METHODS, Vol: 433, Pages: 6-16, ISSN: 0022-1759
McDonald JU, Kaforou M, Clare S, et al., 2016, A Simple Screening Approach To Prioritize Genes for Functional Analysis Identifies a Role for Interferon Regulatory Factor 7 in the Control of Respiratory Syncytial Virus Disease, MSYSTEMS, Vol: 1, ISSN: 2379-5077
Porter JD, Watson J, Roberts LR, et al., 2016, Identification of novel macrolides with antibacterial, anti-inflammatory and type I and III IFN-augmenting activity in airway epithelium, JOURNAL OF ANTIMICROBIAL CHEMOTHERAPY, Vol: 71, Pages: 2767-2781, ISSN: 0305-7453
Russell RF, McDonald JU, Lambert L, et al., 2016, Use of the Microparticle Nanoscale Silicon Dioxide as an Adjuvant To Boost Vaccine Immune Responses against Influenza Virus in Neonatal Mice, JOURNAL OF VIROLOGY, Vol: 90, Pages: 4735-4744, ISSN: 0022-538X
Badamchi-Zadeh A, McKay PF, Holland MJ, et al., 2015, Intramuscular Immunisation with Chlamydial Proteins Induces Chlamydia trachomatis Specific Ocular Antibodies, PLOS ONE, Vol: 10, ISSN: 1932-6203
Kinnear E, Caproni LJ, Tregoning JS, 2015, A Comparison of Red Fluorescent Proteins to Model DNA Vaccine Expression by Whole Animal In Vivo Imaging, PLOS ONE, Vol: 10, ISSN: 1932-6203
Mastelic Gavillet B, Eberhardt CS, Auderset F, et al., 2015, MF59 Mediates Its B Cell Adjuvanticity by Promoting T Follicular Helper Cells and Thus Germinal Center Responses in Adult and Early Life., Journal of Immunology, Vol: 194, Pages: 4836-4845, ISSN: 0022-1767
The early life influenza disease burden calls for more effective vaccines to protect this vulnerable population. Influenza vaccines including the MF59 oil-in-water adjuvant induce higher, broader, and more persistent Ab responses in adults and particularly in young, through yet undefined mechanisms. In this study, we show that MF59 enhances adult murine IgG responses to influenza hemagglutinin (HA) by promoting a potent T follicular helper cells (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. Remarkably, this enhancement of TFH and GC B cells is already fully functional in 3-wk-old infant mice, which were fully protected by HA/MF59 but not HA/PBS immunization against intranasal challenge with the homologous H1N1 (A/California/7/2009) strain. In 1-wk-old neonatal mice, MF59 recruits and activates APCs, efficiently induces CD4(+) effector T cells and primes for enhanced infant responses but induces few fully functional TFH cells, which are mostly follicular regulatory T cells, and poor GC and anti-HA responses. The B cell adjuvanticity of MF59 appears to be mediated by the potent induction of TFH cells which directly controls GC responses both in adult and early life, calling for studies assessing its capacity to enhance the efficacy of influenza immunization in young infants.
Russell RF, McDonald JU, Ivanova M, et al., 2015, Partial Attenuation of Respiratory Syncytial Virus with a Deletion of a Small Hydrophobic Gene Is Associated with Elevated Interleukin-1 beta Responses, JOURNAL OF VIROLOGY, Vol: 89, Pages: 8974-8981, ISSN: 0022-538X
Siggins MK, Gill SK, Langford PR, et al., 2015, PHiD-CV induces anti-Protein D antibodies but does not augment pulmonary clearance of nontypeable Haemophilus influenzae in mice, VACCINE, Vol: 33, Pages: 4954-4961, ISSN: 0264-410X
Veazey RS, Siddiqui A, Klein K, et al., 2015, Evaluation of mucosal adjuvants and immunization routes for the induction of systemic and mucosal humoral immune responses in macaques, HUMAN VACCINES & IMMUNOTHERAPEUTICS, Vol: 11, Pages: 2913-2922, ISSN: 2164-5515
Harker JA, Yamaguchi Y, Culley FJ, et al., 2014, Delayed Sequelae of Neonatal Respiratory Syncytial Virus Infection Are Dependent on Cells of the Innate Immune System, JOURNAL OF VIROLOGY, Vol: 88, Pages: 604-611, ISSN: 0022-538X
Tregoning JS, Kinnear E, 2014, Using Plasmids as DNA Vaccines for Infectious Diseases.
DNA plasmids can be used to induce a protective (or therapeutic) immune response by delivering genes encoding vaccine antigens. That naked DNA (without the refinement of coat proteins or host evasion systems) can cross from outside the cell into the nucleus and be expressed is particularly remarkable given the sophistication of the immune system in preventing infection by pathogens. As a result of the ease, low cost, and speed of custom gene synthesis, DNA vaccines dangle a tantalizing prospect of the next wave of vaccine technology, promising individual designer vaccines for cancer or mass vaccines with a rapid response time to emerging pandemics. There is considerable enthusiasm for the use of DNA vaccination as an approach, but this enthusiasm should be tempered by the successive failures in clinical trials to induce a potent immune response. The technology is evolving with the development of improved delivery systems that increase expression levels, particularly electroporation and the incorporation of genetically encoded adjuvants. This review will introduce some key concepts in the use of DNA plasmids as vaccines, including how the DNA enters the cell and is expressed, how it induces an immune response, and a summary of clinical trials with DNA vaccines. The review also explores the advances being made in vector design, delivery, formulation, and adjuvants to try to realize the promise of this technology for new vaccines. If the immunogenicity and expression barriers can be cracked, then DNA vaccines may offer a step change in mass vaccination.
Walters AA, Kinnear E, Shattock RJ, et al., 2014, Comparative analysis of enzymatically produced novel linear DNA constructs with plasmids for use as DNA vaccines, Gene Therapy, Vol: 21, Pages: 645-652, ISSN: 1476-5462
Everitt AR, Clare S, McDonald JU, et al., 2013, Defining the Range of Pathogens Susceptible to Ifitm3 Restriction Using a Knockout Mouse Model, PLOS ONE, Vol: 8, ISSN: 1932-6203
Garnett JP, Baker EH, Naik S, et al., 2013, Metformin reduces airway glucose permeability and hyperglycaemia-induced Staphylococcus aureus load independently of effects on blood glucose, THORAX, Vol: 68, Pages: 835-845, ISSN: 0040-6376
Garnett JP, Baker EH, Tregoning JS, et al., 2013, Metformin Inhibits Hyperglycemia-Induced Airway Bacterial Growth And Is Associated With Reduced Transepithelial Glucose Permeability, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 187, ISSN: 1073-449X
Mann JFS, Mckay PF, Arokiasamy S, et al., 2013, Mucosal Application of gp140 Encoding DNA Polyplexes to Different Tissues Results in Altered Immunological Outcomes in Mice, PLOS ONE, Vol: 8, ISSN: 1932-6203
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