Laura Denney

University of Oxford, Oxford, ENG, United Kingdom

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Publications (5)30.06 Total impact

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    ABSTRACT: RATIONALE: T cell responses have been implicated in both control and exacerbation of lung injury during influenza A virus (IAV) infection. OBJECTIVES: To examine the breadth and magnitude of influenza-specific CD4+ and CD8+ T cell responses during acute phase of infection. METHODS: Influenza-specific T cell response to the entire pandemic H1N1/09 influenza A virus proteome and T cell-related cytokine levels were measured in blood from previously healthy individuals with mild (n=32) and severe (n=16) IAV infection during the 2009 influenza pandemic. Virus-specific T cell response in lung and blood was also performed in two acutely infected, severely ill patients using fluorescent-conjugated pdmH1N1/09 Matrix-MHC-I tetrameric complexes. MAIN RESULTS: Strong and broad CD4+ but not CD8+ T cell responses were observed in the blood, and were higher in those with severe disease. Antigen-specific CD8+ T cells in the lungs were on average, 45-fold higher compared to blood in both severely ill patients. Paradoxically, in patients with severe disease, IL-17, IL-2, IL-4 and IFN-γ levels were significantly decreased. CONCLUSION: High levels of circulating virus-specific CD4+ T cells to two viral internal proteins (nucleoprotein and matrix) in the first phase of infection is associated with subsequent development of severe IAV infection. This finding could be an early and specific marker for ensuing clinical deterioration. Differential levels of antigen-specific CD8+ T cells in lungs and blood have implications on design and analysis of clinical of trials for T cell vaccines since measurements of T cells in the periphery may not reflect events in the lungs.
    American Journal of Respiratory and Critical Care Medicine 10/2012; · 11.04 Impact Factor
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    ABSTRACT: Neuropathology in multiple sclerosis is closely linked to presence of macrophages in the CNS. Both M1 (inflammatory) and M2 (alternatively activated, noninflammatory) macrophages are found in the inflamed CNS and thought to differentiate from infiltrating monocytes. It is unclear whether the balance of M1 and M2 macrophages can be altered and whether this affects disease outcome. We show in this article that Ly6C(hi) inflammatory monocytes are the early and dominant infiltrating cells in the CNS during experimental autoimmune encephalomyelitis, a model for the acute phase of multiple sclerosis. Activation of invariant NKT (iNKT) cells reduced the frequency of Ly6C(hi) monocytes and increased the proportion of M2 macrophages in the CNS with associated improvement in neurologic impairment. In contrast, iNKT-deficient mice showed higher numbers of Ly6C(hi) monocytes, reduced M2, and much more severe disease. Adoptive transfer of M2-enriched cells to iNKT-deficient mice markedly improved neurologic impairment. In vitro and in vivo experiments showed that iNKT cells promote differentiation of monocytes to M2 macrophages in an IL-4 and CD1d-dependent process. These findings indicate that infiltrating Ly6C(hi) inflammatory monocytes are early players in acute neuroinflammation and that their frequency and differentiation can be influenced by activation of iNKT cells with resultant improvement in disease outcome.
    The Journal of Immunology 06/2012; 189(2):551-7. · 5.52 Impact Factor
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    ABSTRACT: Little is known of how a strong immune response in the lungs is regulated to minimize tissue injury during severe influenza A virus (IAV) infection. Here, using a model of lethal, high-pathogenicity IAV infection, we first show that Ly6C(hi)Ly6G(-) inflammatory monocytes, and not neutrophils, are the main infiltrate in lungs of WT mice. Mice devoid of iNKT cells (Jα18(-/-) mice) have increased levels of inflammatory monocytes, which correlated with increased lung injury and mortality (but not viral load). Activation of iNKT cells correlated with reduction of MCP-1 levels and improved outcome. iNKT cells were able to selectively lyse infected, MCP-1-producing monocytes in vitro, in a CD1d-dependent process. Our study provides a detailed profile and kinetics of innate immune cells in the lungs during severe IAV infection, highlighting inflammatory monocytes as the major infiltrate and identifying a role for iNKT cells in control of these cells and lung immune-pathology.
    Journal of leukocyte biology 03/2012; 91(3):357-68. · 4.99 Impact Factor
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    ABSTRACT: The cause of severe disease in some patients infected with pandemic influenza A virus is unclear. We present the cellular immunology profile in the blood, and detailed clinical (and post-mortem) findings of three patients with rapidly progressive infection, including a pregnant patient who died. The striking finding is of reduction in natural killer (NK) cells but preservation of activated effector CD8 T lymphocytes; with viraemia in the patient who had no NK cells. Comparison with control groups suggests that the reduction of NK cells is unique to these severely ill patients. Our report shows markedly reduced NK cells in the three patients that we sampled and raises the hypothesis that NK may have a more significant role than T lymphocytes in controlling viral burden when the host is confronted with a new influenza A virus subtype.
    PLoS ONE 01/2010; 5(5):e10675. · 3.53 Impact Factor
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    ABSTRACT: Invariant NKT (iNKT) cells have an indubitable role in antiviral immunity, although the mechanisms by which these cells exert their functions are not fully elucidated. With the emerging importance of high-pathogenicity influenza A virus infections in humans, we questioned whether iNKT cells contribute to immune defence against influenza A virus and whether activation of these cells influences outcome. We show that activation of iNKT cells with alpha-galactosylceramide (alpha-GC) during influenza virus infection transiently enhanced early innate immune response without affecting T cell immunity, and reduced early viral titres in lungs of C57BL/6 mice. This is accompanied by a better disease course with improved weight loss profile. Temporal changes in iNKT cells in the liver, blood and lungs suggest activation and migration of iNKT cells from the liver to the lungs in mice that were administered alpha-GC. Improvement in viral titres appears dependent on activation of iNKT cells via the intraperitoneal route since intranasal administration of alpha-GC did not have the same effect. We conclude that activation of iNKT cells enhances early innate immune response in the lungs and contribute to antiviral immunity and improved disease course in influenza A virus infection.
    European Journal of Immunology 07/2008; 38(7):1913-22. · 4.97 Impact Factor