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    ABSTRACT: Adoptive transfer of antigen-specific, in vitro-induced Foxp3+ Treg (iTreg) cells protects against autoimmune disease. To generate antigen-specific iTreg cells at high purity, however, remains a challenge. Whereas polyclonal T cell stimulation with anti-CD3 and anti- CD28 antibody yields Foxp3+ iTreg cells at a purity of 90-95 %, antigen-induced iTreg cells typically do not exceed a purity of 65-75 %, even in a TCR-transgenic model. In a similar vein to thymic Treg cell selection, iTreg cell differentiation is influenced not only by antigen recognition and the availability of TGF- but also by co-factors including costimulation and adhesion molecules. In this study, we demonstrate that blockade of the T cell integrin Leukocyte Function-associated Antigen-1 (LFA-1) during antigen-mediated iTreg cell differentiation augments Foxp3 induction, leading to approximately 90 % purity of Foxp3+ iTreg cells. This increased efficacy not only boosts the yield of Foxp3+ iTreg cells, it also reduces contamination with activated effector T cells, thus improving the safety of adoptive transfer immunotherapy.
    Journal of Immunological Methods 08/2014; DOI:10.1016/j.jim.2014.07.012
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    ABSTRACT: Tumor suppressor genes such as RASSF1A are often epigenetically repressed by DNA hypermethylation in neuroblastoma, where the MYCN proto-oncogene is frequently amplified. MYC has been shown to associate with DNA methyltransferases, thereby inducing transcriptional repression of target genes, which suggested that MYCN might play a similar mechanistic role in the hypermethylation of tumor suppressor genes in neuroblastoma. This study tested that hypothesis by using co-immunoprecipitation and ChIP to investigate MYCN-DNA methyltransferase interactions, together with MYCN knock-down and over-expression systems to examine the effect of MYCN expression changes on gene methylation, employing both candidate gene and genome-wide assays. We show that MYCN interacts with DNA methyltransferases and is recruited to the promoter region of RASSF1A. However, using four model systems, we showed that long-term silencing of MYCN induces only a small loss of DNA methylation at the RASSF1A promoter in MYCN amplified neuroblastoma cell lines and over-expression of MYCN does not induce any DNA methylation, suggesting that MYCN is not critical for DNA hypermethylation in neuroblastoma. © 2012 Wiley Periodicals, Inc.
    Molecular Carcinogenesis 05/2014; 53(5). DOI:10.1002/mc.21994
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    ABSTRACT: Antibiotic use in infancy disrupts gut microflora during a critical period for immune system development. It is hypothesized that this could predispose to the development of allergic diseases. We investigated the associations of antibiotic use in the first 2 yr of life with the development of asthma, eczema or hay fever by age 7.5 yr in a longitudinal birth cohort. Subjects were 4952 children from the Avon Longitudinal Study of Parents and Children (ALSPAC). Child antibiotic use and asthma, eczema and hay fever symptoms were maternally reported. Atopy was assessed by skin prick tests at age 7.5 yr. The total number of antibiotic courses was considered as the main exposure. Data were analysed using multivariate logistic regression. Children reported to have taken antibiotics during infancy (0-2 yr) were more likely to have asthma at 7.5 yr (OR 1.75, 95% CI 1.40-2.17), and the odds (OR, [95% CI]) increased with greater numbers of courses: once 1.11 [0.84-1.48]; twice 1.50 [1.14-1.98]; three times 1.79 [1.34-2.40]; four times or more 2.82 [2.19-3.63]. Increased antibiotic use was also associated with higher odds of eczema and hay fever but not atopy. The effect appeared to be associated with cumulative rather than a critical period of exposure during the first 2 yr. A robust and dose-dependent association was found between antibiotic use in the first 2 yr of life and asthma at age 7.5 yr but did not appear to be mediated through an association with atopy.
    Pediatric Allergy and Immunology 12/2013; DOI:10.1111/pai.12153
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    ABSTRACT: The polysaccharides (PS) surrounding encapsulated bacteria are generally unable to activate T cells and hence do not induce B cell memory (BMEM). PS conjugate vaccines recruit CD4(+) T cells via a carrier protein, such as tetanus toxoid (TT), resulting in the induction of PS-specific BMEM. However, the requirement for T cells in the subsequent activation of the BMEM at the time of bacterial encounter is poorly understood, despite having critical implications for protection. We demonstrate that the PS-specific BMEM induced in humans by a meningococcal serogroup C PS (Men C)-TT conjugate vaccine conform to the isotype-switched (IgG(+)CD27(+)) rather than the IgM memory (IgM(+)CD27(+)) phenotype. Both Men C and TT-specific BMEM require CD4(+) T cells to differentiate into plasma cells. However, noncognate bystander T cells provide such signals to PS-specific BMEM with comparable effect to the cognate T cells available to TT-specific BMEM. The interaction between the two populations is contact-dependent and is mediated in part through CD40. Meningococci drive the differentiation of the Men C-specific BMEM through the activation of bystander T cells by bacterial proteins, although these signals are enhanced by T cell-independent innate signals. An effect of the TT-specific T cells activated by the vaccine on unrelated BMEM in vivo is also demonstrated. These data highlight that any protection conferred by PS-specific BMEM at the time of bacterial encounter will depend on the effectiveness with which bacterial proteins are able to activate bystander T cells. Priming for T cell memory against bacterial proteins through their inclusion in vaccine preparations must continue to be pursued.
    The Journal of Immunology 11/2013; 191(12). DOI:10.4049/jimmunol.1203254
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    ABSTRACT: Pneumococcal disease is associated with a particularly high morbidity and mortality amongst adults in HIV endemic countries. Our previous findings implicating a B-cell defect in HIV-infected children from the same population led us to comprehensively characterize B-cell subsets in minimally symptomatic HIV-infected Malawian adults and investigate the isotype-switched IgG memory B-cell immune response to the pneumococcus. We show that similar to vertically acquired HIV-infected Malawian children, horizontally acquired HIV infection in these adults is associated with IgM memory B-cell (CD19(+) CD27(+) IgM(+) IgD(+)) depletion, B-cell activation and impairment of specific IgG B-cell memory to a range of pneumococcal proteins. Our data suggest that HIV infection affects both T-cell independent and T-cell dependent B-cell maturation, potentially leading to impairment of humoral responses to extracellular pathogens such as the pneumococcus, and thus leaving this population susceptible to invasive disease.
    PLoS ONE 11/2013; 8(11):e78592. DOI:10.1371/journal.pone.0078592
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    ABSTRACT: Cartilage injuries and osteoarthritis are a leading cause of disability in developed countries. The regeneration of damaged articular cartilage using cell transplantation or tissue engineering holds much promise but requires the identification of an appropriate cell source with a high proliferative propensity and consistent chondrogenic capacity. Human fetal mesenchymal stem cells (MSCs) have been isolated from a range of perinatal tissues including first trimester bone marrow and have demonstrated enhanced expansion and differentiation potential. However their ability to form mature chondrocytes for use in cartilage tissue engineering has not been clearly established. Here we compare the chondrogenic potential of human MSCs isolated from fetal and adult bone marrow and show distinct differences in their responsiveness to specific growth factors. Transforming growth factor beta 3 (TGFβ3) induced chondrogenesis in adult but not fetal MSCs. In contrast, bone morphogenetic protein 2 (BMP2) induced chondrogenesis in fetal but not adult MSCs. When fetal MSCs co-stimulated with BMP2 and TGFβ3 were used for cartilage tissue engineering they generated tissue with type II collagen and proteoglycan content comparable to adult MSCs treated with TGFβ3 alone. Investigation of the TGFβ/BMP signalling pathway showed that TGFβ3 induced phosphorylation of SMAD3 in adult but not fetal MSCs. These findings demonstrate that the initiation of chondrogenesis is modulated by distinct signalling mechanisms in fetal and adult MSCs. This study establishes the feasibility of using fetal MSCs in cartilage repair applications and proposes their potential as an in vitro system for modelling chondrogenic differentiation and skeletal development studies.
    Stem cells and development 10/2013; DOI:10.1089/scd.2013.0301
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    ABSTRACT: It has been reported that targeted disruption of ampDI or mrcA causes β-lactamase hyper-production in Stenotrophomonas maltophilia. Here we show that β-lactamase hyper-producing laboratory selected mutants and clinical isolates can have wild-type ampDI and mrcA genes, implicating mutation of at least one additional gene in this phenotype. The involvement of mutations at multiple loci in the activation of β-lactamase production in S. maltophilia reveals that there are significant deviations from the Enterobacterial paradigm of AmpR-mediated control of β-lactamase induction. We do show, however, that S. maltophilia ampDI can complement a mutation in Escherichia coli ampD. This suggests that an anhydro-muropeptide degradation product of peptidoglycan is used to activate AmpR in S. maltophilia as is also the case in enteric bacteria.
    Antimicrobial Agents and Chemotherapy 08/2013; DOI:10.1128/AAC.01446-13
  • Vaccine 08/2013; 31(43). DOI:10.1016/j.vaccine.2013.07.046
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    ABSTRACT: The Wnt/β-catenin signalling and autophagy pathways each play important roles during development, adult tissue homeostasis and tumorigenesis. Here we identify the Wnt/β-catenin signalling pathway as a negative regulator of both basal and stress-induced autophagy. Manipulation of β-catenin expression levels in vitro and in vivo revealed that β-catenin suppresses autophagosome formation and directly represses p62/SQSTM1(encoding the autophagy adaptor p62) via TCF4. Furthermore, we show that during nutrient deprivation β-catenin is selectively degraded via the formation of a β-catenin-LC3 complex, attenuating β-catenin/TCF-driven transcription and proliferation to favour adaptation during metabolic stress. Formation of the β-catenin-LC3 complex is mediated by a W/YXXI/L motif and LC3-interacting region (LIR) in β-catenin, which is required for interaction with LC3 and non-proteasomal degradation of β-catenin. Thus, Wnt/β-catenin represses autophagy and p62 expression, while β-catenin is itself targeted for autophagic clearance in autolysosomes upon autophagy induction. These findings reveal a regulatory feedback mechanism that place β-catenin at a key cellular integration point coordinating proliferation with autophagy, with implications for targeting these pathways for cancer therapy.
    The EMBO Journal 06/2013; DOI:10.1038/emboj.2013.123
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    ABSTRACT: A series of studies have reported a constant global rise in the incidence of type 1 diabetes. Epidemiological and immunological studies have demonstrated that environmental factors may influence the pathogenesis, leading to a cell-mediated pancreatic β cell destruction associated with humoral immunity. The search for the triggering factor(s) has been going on for the past century and yet it is still unknown. This review provides an overview of some of the most well-known theories found in the literature: hygiene, viral, vitamin D deficiency, breast milk, and cow's milk hypotheses. Although the hygiene hypothesis appears to be the most promising, positive evidence from animal, human and epidemiological studies precludes us from completely discarding any of the other hypotheses. Moreover, due to contrasting evidence in the literature, a single factor is unlikely to cause an increase in diabetes all over the world; which suggests that a multifactorial process might be involved. Although the immunological mechanisms are still unclear, there seems to be some overlap between the various hypotheses. It is thought that the emphasis should be shifted from a single to a multifactorial process, and perhaps consider the 'balance shift' model as a possible explanation for the rise in incidence in type 1 diabetes.
    Journal of Molecular Endocrinology 06/2013; DOI:10.1530/JME-13-0067
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