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Martin F.,Center for Immunology and Infection | Taylor G.P.,Imperial College London
AIDS Reviews | Year: 2011

Over the twenty-five years since the association of human T-cell lymphotropic virus type 1 infection with tropical spastic paraparesis, little progress has been made in the treatment of this chronic debilitating condition. The purpose of this review is to highlight the most informative results and to identify the most promising candidates for further study. Although many small observational studies have been reported, only twice have the positive data been tested in randomized controlled studies. In the first study, interferon-alpha 3 MU was found to be better than 0.3 or 1 MU over four weeks, whilst zidovudine plus lamivudine performed no better than placebo after 24-48 weeks of therapy in the second study. Preliminary data from studies of immunomodulatory therapy including cyclosporine and monoclonal antibodies to CD25 and interleukin-15 are encouraging and further comparative studies are indicated with the combination of antiretroviral therapy with histone deacetylation inhibition, which has been shown to reduce simian T-lymphotropic virus type 1 proviral load in baboons, unless this proves unsuccessful in human T-cell lymphotropic virus type 1 infection. Source

Li Z.,Durham University | Li Z.,Center for Immunology and Infection | Hodgkinson T.,University of Manchester | Gothard E.J.,Center for Immunology and Infection | And 14 more authors.
Nature Communications | Year: 2016

Notch has a well-defined role in controlling cell fate decisions in the embryo and the adult epidermis and immune systems, yet emerging evidence suggests Notch also directs non-cell-autonomous signalling in adult tissues. Here, we show that Notch1 works as a damage response signal. Epidermal Notch induces recruitment of immune cell subsets including RORγ + ILC3s into wounded dermis; RORγ + ILC3s are potent sources of IL17F in wounds and control immunological and epidermal cell responses. Mice deficient for RORγ + ILC3s heal wounds poorly resulting from delayed epidermal proliferation and macrophage recruitment in a CCL3-dependent process. Notch1 upregulates TNFα and the ILC3 recruitment chemokines CCL20 and CXCL13. TNFα, as a Notch1 effector, directs ILC3 localization and rates of wound healing. Altogether these findings suggest that Notch is a key stress/injury signal in skin epithelium driving innate immune cell recruitment and normal skin tissue repair. Source

Lim E.-K.,Center for Immunology and Infection | Mitchell P.J.,Center for Immunology and Infection | Brown N.,Center for Immunology and Infection | Drummond R.A.,University of Aberdeen | And 3 more authors.
Journal of Biological Chemistry | Year: 2013

Background: Plant natural products typically contain regiospecific modifications in their side chains that lead to different bioactivities. Results: Only 3-O-methylated flavonols enhance IL-1β production in THP-1 cells costimulated with the Toll-like receptor 2 agonist Pam3CSK4. Conclusion: Regiospecific methylation of flavonols controls their bioactivity as immunomodulators. Significance: This study provides a platform to explore the use of regiospecific-modified natural products as novel immunomodulators. © 2013 by The American Society for Biochemistry and Molecular Biology, Inc. Source

Alden K.,Center for Immunology and Infection | Alden K.,University of York | Timmis J.,University of York | Andrews P.S.,University of York | And 2 more authors.
Frontiers in Immunology | Year: 2012

The use of genetic tools, imaging technologies and ex vivo culture systems has provided significant insights into the role of tissue inducer cells and associated signaling pathways in the formation and function of lymphoid organs. Despite advances in experimental tech- nologies, the molecular and cellular process orchestrating the formation of a complex three-dimensionaltissueisdifficulttodissectusingcurrentapproaches. Therefore, arobust set of simulation tools have been developed to model the processes involved in lymphoid tissue development. Specifically, the role of different tissue inducer cell populations in the dynamic formation of Peyer's patches has been examined. Utilizing approaches from sys- tems engineering, an unbiased model of lymphoid tissue inducer cell function has been developed that permits the development of emerging behaviors that are statistically not different from that observed in vivo. These results provide the confidence to utilize statis- tical methods to explore how the simulator predicts cellular behavior and outcomes under different physiological conditions. Such methods, known as sensitivity analysis techniques, can provide insight into when a component part of the system (such as a particular cell type, adhesion molecule, or chemokine) begins to have an influence on observed behavior, and quantifies the effect a component part has on the end result: the formation of lymphoid tissue. Through use of such a principled approach in the design, calibration, and analysis of a computer simulation, a robust in silico tool can be developed which can both further the understanding of a biological system being explored, and act as a tool for the generation of hypotheses which can be tested utilizing experimental approaches. © 2012 Alden, Timmis, Andrews, Veiga-Fernandes and Coles. Source

Price H.P.,Center for Immunology and Infection | Guther M.L.S.,University of Dundee | Ferguson M.A.J.,University of Dundee | Smith D.F.,Center for Immunology and Infection
Molecular and Biochemical Parasitology | Year: 2010

The enzyme myristoyl-CoA:protein N-myristoyltransferase (NMT) catalyses the co-translational covalent attachment of the fatty acid myristate to the N-terminus of target proteins. NMT is known to be essential for viability in Trypanosoma brucei and Leishmania major. Here we describe phenotypic analysis of T. brucei bloodstream form cells following knockdown of NMT expression by tetracycline-inducible RNA interference. Cell death occurs from 72 h post-induction, with approximately 50% of cells displaying a defect in endocytic uptake by this time. The majority of these induced cells do not have an enlarged flagellar pocket typical of a block in endocytosis but vesicle accumulation around the flagellar pocket indicates a defect in vesicular progression following endocytic fusion. Induced parasites have a wild-type or slightly enlarged Golgi apparatus, unlike the phenotype of cells with reduced expression of a major N-myristoylated protein, ARL1. Critically we show that following NMT knockdown, T. brucei bloodstream form cells are unable to establish an infection in a mouse model, therefore providing further validation of this enzyme as a target for drug development. © 2009 Elsevier B.V. All rights reserved. Source

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