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Search Results: 1 - 10 of 410735 matches for " Stephen M. Anderton "
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Peptide immunotherapy for childhood allergy - addressing translational challenges
Karen J Mackenzie, Stephen M Anderton, Jürgen Schwarze
Clinical and Translational Allergy , 2011, DOI: 10.1186/2045-7022-1-13
Abstract: Allergic disease including atopic eczema, allergic rhinitis, allergic asthma and food allergy causes significant patient morbidity and economic costs to healthcare systems [1,2]. Current clinical management primarily relies on allergen avoidance, treating symptoms as they arise (often using medications such as β2 agonist inhalers, antihistamines and adrenaline) and generalised suppression of immune responses (e.g. using corticosteroids). Therapeutic blockade of cytokines such as interleukin-5 (IL-5) and of IgE have had varied clinical results and such approaches are reserved for highly selected patient groups at present [3-5]. Many allergic patients will first experience symptoms during childhood [6] and allergic sensitisation may begin very early in infancy, even prenatally [7,8]. Children with atopy are at risk of developing new sensitisations and additional allergic conditions as they get older [1,9]. Identifying atopic children early and modifying disease progression is therefore a hugely attractive therapeutic goal [10].Evidence suggests a key role for CD4+ T cells, particularly the T helper (Th) 2 subset, in allergy. These cells express the transcription factor GATA-binding protein 3 (GATA-3) and can produce allergy-associated cytokines such as IL-4, IL-5 and IL-13 which are implicated in a host of allergic responses such as eosinophil recruitment and airway hyperreactivity [reviewed in [11]]. Th2 cells also provide B cells with help, driving immunoglobulin class-switching towards allergen-specific IgE [11]. Less commonly, and often in concert with Th2 cells, other helper subsets such as Th1, Th17 and Th9 cells have also been implicated in the pathogenesis of allergic asthma in some patients [reviewed in [12]]. Therapeutic targeting of allergen-reactive CD4+ T cells therefore has the capacity to abrogate downstream allergic responses [11]. One way of doing this is through specific immunotherapy (SIT) which targets CD4+ T cells via the administration of protein
T Cells at the Site of Autoimmune Inflammation Show Increased Potential for Trogocytosis
Bettina Haastert, Richard J. Mellanby, Stephen M. Anderton, Richard A. O'Connor
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0081404
Abstract: CD4+ T cells acquire membrane fragments from antigen-presenting-cells via a process termed trogocytosis. Identifying which CD4+ T cells undergo trogocytosis in co-culture with Ag-loaded APC can enrich for antigen-reactive T cells without knowledge of their fine specificity or cytokine-production profiles. We sought to assess the suitability of this method to identify disease relevant effector and regulatory T cells during autoimmune inflammation. Trogocytosis efficiently identified MBP-reactive T cells in vitro and ex-vivo following immunization. However, Foxp3+ regulatory T cells constitutively displayed a higher rate of trogocytosis than their Foxp3- counterparts which limits the potential of trogocytosis to identify antigen-reactive Treg cells. During inflammation a locally elevated rate of trogocytosis (seen in both effector and regulatory T cells isolated from the inflamed CNS) precludes the use of trogocytosis as a measure of antigenic reactivity among cells taken from inflammatory sites. Our results indicate trogocytosis detection can enrich for Ag-reactive conventional T cells in the periphery but is limited in its ability to identify Ag-reactive Treg or T effector cells at sites of inflammation. Increased trogocytosis potential at inflammatory sites also draws into the question the biological significance of this phenomenon during inflammation, in Treg mediated suppression and for the maintenance of tolerance in health and disease.
Recognition of a High Affinity MHC Class I-Restricted Epitope of Myelin Oligodendrocyte Glycoprotein by CD8+ T Cells Derived from Autoantigen-Deficient Mice
Melanie D. Leech,Antonio Carrillo-Vico,Roland S. Liblau,Stephen M. Anderton
Frontiers in Immunology , 2011, DOI: 10.3389/fimmu.2011.00017
Abstract: CD4+ T cells have a well-defined pathogenic role in experimental autoimmune encephalomyelitis, the rodent model of multiple sclerosis (MS), yet CD8+ T cells are commonly found in MS lesions. To determine whether immunological tolerance might impact differently on CD4+ versus CD8+ T cells, we studied T cell responses in mice genetically deficient for the central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG) versus wild type (WT) C57BL/6 mice. We show that MOG?/? mice have enhanced sensitivity to immunization with the immunodominant peptide of MOG (35–55), as evidenced by increased expansion of both CD4+ and CD8+ T cell subsets. Most strikingly, CD8+ T cells from MOG?/? mice responded to a novel T cell epitope which binds to MHC class I with high affinity. Despite this, MOG-responsive CD8+ T cells sourced from either WT or MOG?/? mice failed to initiate CNS inflammation upon transfer to MOG-sufficient mice. In our hands, this capacity was only found in CD4+ T cells. However, MOG?/? CD4+ cells did not show greater pathogenic activity than their WT counterparts. Our data indicate that, in the presence of endogenous MOG, CD8+ T cells capable of responding to a MHC class I-restricted epitope that can be stably expressed are subject to rigorous control through central and/or peripheral tolerance.
Modification of the FoxP3 Transcription Factor Principally Affects Inducible T Regulatory Cells in a Model of Experimental Autoimmune Encephalomyelitis
Johan Verhagen, Bronwen R. Burton, Graham J. Britton, Ella R. Shepard, Stephen M. Anderton, David C. Wraith
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0061334
Abstract: T regulatory (Treg) cells expressing the transcription factor FoxP3 play a key role in protection against autoimmune disease. GFP-FoxP3 reporter mice have been used widely to study the induction, function and stability of both thymically- and peripherally-induced Treg cells. The N-terminal modification of FoxP3, however, affects its interaction with transcriptional co-factors; this can alter Treg cell development and function in certain self-antigen specific animal models. Interestingly, Treg cell function can be negatively or positively affected, depending on the nature of the model. In this study, we focused on the effect of the GFP-FoxP3 reporter on Treg cell development and function in the Tg4 mouse model. In this model, T cells express a transgenic T cell receptor (TCR) specific for the Myelin Basic Protein (MBP) peptide Ac1-9, making the animals susceptible to experimental autoimmune encephalomyelitis (EAE), a disease akin to multiple sclerosis in humans. Unlike diabetes-susceptible mice, Tg4 FoxP3gfp mice did not develop spontaneous autoimmune disease and did not demonstrate augmented susceptibility to induced disease. Concurrently, thymic generation of natural Treg cells was not negatively affected. The induction of FoxP3 expression in naive peripheral T cells was, however, significantly impaired as a result of the transgene. This study shows that the requirements for the interaction of FoxP3 with co-factors, which governs its regulatory ability, differ not only between natural and inducible Treg cells but also between animal models of diseases such as diabetes and EAE.
Ischemic Preconditioning in the Liver Is Independent of Regulatory T Cell Activity
Luke R. Devey, James A. Richards, Richard A. O’Connor, Gary Borthwick, Spike Clay, A. Forbes Howie, Stephen J. Wigmore, Stephen M. Anderton, Sarah E. M. Howie
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0049647
Abstract: Ischemic preconditioning (IPC) protects organs from ischemia reperfusion injury (IRI) through unknown mechanisms. Effector T cell populations have been implicated in the pathogenesis of IRI, and T regulatory cells (Treg) have become a putative therapeutic target, with suggested involvement in IPC. We explored the role of Treg in hepatic IRI and IPC in detail. IPC significantly reduced injury following ischemia reperfusion insults. Treg were mobilized rapidly to the circulation and liver after IRI, but IPC did not further increase Treg numbers, nor was it associated with modulation of circulating pro-inflammatory chemokine or cytokine profiles. We used two techniques to deplete Treg from mice prior to IRI. Neither Treg depleted FoxP3.LuciDTR mice, nor wildtyoe mice depleted of Tregs with PC61, were more susceptible to IRI compared with controls. Despite successful enrichment of Treg in the liver, by adoptive transfer of both iTreg and nTreg or by in vivo expansion of Treg with IL-2/anti-IL-2 complexes, no protection against IRI was observed.We have explored the role of Treg in IRI and IPC using a variety of techniques to deplete and enrich them within both the liver and systemically. This work represents an important negative finding that Treg are not implicated in IPC and are unlikely to have translational potential in hepatic IRI.
Internal evaluation of a physically-based distributed model using data from a Mediterranean mountain catchment
S. P. Anderton,J. Latron,S. M. White,P. Llorens
Hydrology and Earth System Sciences (HESS) & Discussions (HESSD) , 2002,
Abstract: An evaluation of the performance of a physically-based distributed model of a small Mediterranean mountain catchment is presented. This was carried out using hydrological response data, including measurements of runoff, soil moisture, phreatic surface level and actual evapotranspiration. A-priori model parameterisation was based as far as possible on property data measured in the catchment. Limited model calibration was required to identify an appropriate value for terms controlling water loss to a deeper regional aquifer. The model provided good results for an initial calibration period, when judged in terms of catchment discharge. However, model performance for runoff declined substantially when evaluated against a consecutive, rather drier, period of data. Evaluation against other catchment responses allowed identification of the problems responsible for the observed lack of model robustness in flow simulation. In particular, it was shown that an incorrect parameterisation of the soil water model was preventing adequate representation of drainage from soils during hydrograph recessions. This excess moisture was then being removed via an overestimation of evapotranspiration. It also appeared that the model underestimated canopy interception. The results presented here suggest that model evaluation against catchment scale variables summarising its water balance can be of great use in identifying problems with model parameterisation, even for distributed models. Evaluation using spatially distributed data yielded less useful information on model performance, owing to the relative sparseness of data points, and problems of mismatch of scale between the measurement and the model grid. Keywords: physically-based distributed model, SHETRAN, parameterisation, Mediterranean mountain catchment, internal evaluation, multi-response
Epstein-Barr Virus Latency in B Cells Leads to Epigenetic Repression and CpG Methylation of the Tumour Suppressor Gene Bim
Kostas Paschos,Paul Smith,Emma Anderton,Jaap M. Middeldorp,Robert E. White,Martin J. Allday
PLOS Pathogens , 2009, DOI: 10.1371/journal.ppat.1000492
Abstract: In human B cells infected with Epstein-Barr virus (EBV), latency-associated virus gene products inhibit expression of the pro-apoptotic Bcl-2-family member Bim and enhance cell survival. This involves the activities of the EBV nuclear proteins EBNA3A and EBNA3C and appears to be predominantly directed at regulating Bim mRNA synthesis, although post-transcriptional regulation of Bim has been reported. Here we show that protein and RNA stability make little or no contribution to the EBV-associated repression of Bim in latently infected B cells. However, treatment of cells with inhibitors of histone deacetylase (HDAC) and DNA methyltransferase (DNMT) enzymes indicated that epigenetic mechanisms are involved in the down-regulation of Bim. This was initially confirmed by chromatin immunoprecipitation analysis of histone acetylation levels on the Bim promoter. Consistent with this, methylation-specific PCR (MSP) and bisulphite sequencing of regions within the large CpG island located at the 5′ end of Bim revealed significant methylation of CpG dinucleotides in all EBV-positive, but not EBV-negative B cells examined. Genomic DNA samples exhibiting methylation of the Bim promoter included extracts from a series of explanted EBV-positive Burkitt's lymphoma (BL) biopsies. Subsequent analyses of the histone modification H3K27-Me3 (trimethylation of histone H3 lysine 27) and CpG methylation at loci throughout the Bim promoter suggest that in EBV-positive B cells repression of Bim is initially associated with this repressive epigenetic histone mark gradually followed by DNA methylation at CpG dinucleotides. We conclude that latent EBV initiates a chain of events that leads to epigenetic repression of the tumour suppressor gene Bim in infected B cells and their progeny. This reprogramming of B cells could have important implications for our understanding of EBV persistence and the pathogenesis of EBV-associated disease, in particular BL.
Personality Fit and Positive Interventions: Extraverted and Introverted Individuals Benefit from Different Happiness Increasing Strategies  [PDF]
Stephen M. Schueller
Psychology (PSYCH) , 2012, DOI: 10.4236/psych.2012.312A172
Abstract:

The current investigation examined if introverts and extraverts benefit differentially from specific positive psychology interventions. Across two studies participants completed various interventions: three good things, gratitude visit, savoring, signature strength, and active-constructive responding. In study 1, each participant (N = 150) completed 1 of the 5 interventions over a one-week period. All 5 interventions led to increases in happiness, t(144) = 3.80, p < .001, and reductions in depressive symptoms t(144) = 5.20, p <.001. Neither exercise was more beneficial overall. The results of an ANCOVA (with baseline levels as a covariate) found that the interaction term for extraversion and condition was at a trend level F(4, 139) = 2.36, p = .056 and planned contrast analyses supported a pattern of person-activity fit. Extraverts benefited more from the gratitude visit and savoring exercises, whereas introverts benefited more from the active-constructive responding, signature strength, and three good things exercises. In study 2, participants (N = 85) were assigned to one of three groups: the gratitude visit performed either in-person, over the phone, or via mail. Participants completed each exercise over a one-week period. No differential efficacy was found for the 3 interventions, F(1,

Secondary Ion Mass Spectrometry Imaging of Dictyostelium discoideum Aggregation Streams
John Daniel DeBord, Donald F. Smith, Christopher R. Anderton, Ron M. A. Heeren, Ljiljana Pa?a-Toli?, Richard H. Gomer, Francisco A. Fernandez-Lima
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0099319
Abstract: High resolution imaging mass spectrometry could become a valuable tool for cell and developmental biology, but both, high spatial and mass spectral resolution are needed to enable this. In this report, we employed Bi3 bombardment time-of-flight (Bi3 ToF-SIMS) and C60 bombardment Fourier transform ion cyclotron resonance secondary ion mass spectrometry (C60 FTICR-SIMS) to image Dictyostelium discoideum aggregation streams. Nearly 300 lipid species were identified from the aggregation streams. High resolution mass spectrometry imaging (FTICR-SIMS) enabled the generation of multiple molecular ion maps at the nominal mass level and provided good coverage for fatty acyls, prenol lipids, and sterol lipids. The comparison of Bi3 ToF-SIMS and C60 FTICR-SIMS suggested that while the first provides fast, high spatial resolution molecular ion images, the chemical complexity of biological samples warrants the use of high resolution analyzers for accurate ion identification.
Lack of Evidence for Decreased Protein Stability in the 2397 (Met) Haplotype of the Leucine Rich Repeat Kinase 2 Protein Implicated in Parkinson’s Disease  [PDF]
Ryan S. Anderton, Lauren Hill, Rhiannon Morris, Frank L. Mastaglia, Wayne Greene, Sherif Boulos
Advances in Parkinson's Disease (APD) , 2017, DOI: 10.4236/apd.2017.64012
Abstract:
Missense mutations in the leucine rich repeat kinase 2 (LRRK2) gene are the leading genetic cause of autosomal dominant familial Parkinson’s disease. We previously reported that two mutations within the ROC domain, namely R1441C and A1442P, exhibit increased protein degradation leading to lowered steady state LRRK2 protein levels in HEK293 cells. More recently, the common WD40 domain LRRK2 haplotype, Met2397, which is a risk factor for Crohn’s disease, has been shown to lower steady state protein levels in HEK293 cells. In view of recent evidence implicating LRRK2 and inflamemation in PD, we investigated the effects of Met2397 on LRRK2 expression, and compared them to the Thr2397 variant and other LRRK2 mutants. In this study, we transfected HEK293 cells with plasmid constructs encoding the different LRRK2 variants, and analyzed the resulting protein levels by Western blot and flow cytometry. Here we found that both the Met2397 and Thr2397 haplotypes yield similar levels of LRRK2 protein expression and do not appear to impact cell viability in HEK293 cells, compared to other LRRK mutants. Thus, we have concluded that the Met2397 haplotype is unlikely to play a role in LRRK2 mediated or idiopathic PD.
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