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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.
    Full-text · Article · Aug 2014 · Journal of Immunological Methods
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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.
    No preview · Article · May 2014 · Molecular Carcinogenesis
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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.
    Full-text · Article · Dec 2013 · Pediatric Allergy and Immunology
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