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    ABSTRACT: Autoimmune hepatitis (AIH) is an important cause of severe liver disease and is associated with both quantitative and qualitative regulatory T cell (Treg) impairments. We have shown that Tregs express CD39, an ectonucleotidase responsible for extracellular nucleotide hydrolysis, culminating in the production of immunosuppressive adenosine. In this study, we describe multiple CD39(pos) Treg defects that potentially contribute to the impaired immuno-regulation that is characteristic of AIH. We have examined the frequency and phenotype of CD39(pos) Tregs by flow cytometry and measured their ectonucleotidase activity. The capacity of CD4(pos) CD25(high) , CD4(pos) CD25(high) CD39(pos) and CD4(pos) CD25(high) CD39(neg) subsets to suppress both proliferation of effector T cells and IL17 production was evaluated. In AIH, CD39(pos) Tregs are decreased in frequency, exhibit limited adenosine triphosphate (ATP)/adenosine diphosphate (ADP) hydrolysis activity and fail to suppress IL17 production by effector CD4 T cells. Moreover, these CD39(pos) Tregs display a more pro-inflammatory profile in AIH, which is characterised by elevated CD127 positivity, and a greater propensity to produce IFNγ or IL17 upon challenge with pro-inflammatory stimuli. In AIH CD39(pos) Tregs are decreased in number, fail to adequately hydrolyse pro-inflammatory nucleotides and do not suppress efficiently IL17 production by effector CD4 T cells. CD39(pos) Tregs show plasticity and are unstable upon pro-inflammatory challenge, suggesting that defective immuno-regulation in AIH might result not only from reduced Treg number and function but also from increased conversion of Tregs into effector cells. (HEPATOLOGY 2013.).
    Hepatology 03/2014; 59(3). DOI:10.1002/hep.26583
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    ABSTRACT: CD46 is an important regulator of the complement system by preventing unwanted deposition of the complement activation products and opsonins C3b/C4b onto self-tissue. Recently, intracellular signals mediated by CD46 activation on several distinct human cell types have demonstrated that CD46 also plays decisive roles in immuneregulation. The growing recognition of CD46 as key regulator in several vital biological processes, led to increased demand in sensitive methods for monitoring CD46 expression and changes thereof on cells and in tissues. Here we describe a method, which allows for studying CD46 expression on the surface of cells using specific antibodies in combination with fluorescence-activated cell sorting (FACS) analysis.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1100:329-39. DOI:10.1007/978-1-62703-724-2_27
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    ABSTRACT: CD59 is the single regulator of the terminal complement pathway. It has been implicated in disease such as Paroxysmal nocturnal hemoglobinuria (PMH) and cancer. Expression of CD59 protects normal and malignant cells from the cytotoxic potential of the complement system. Here we describe a method, which allows for studying its expression on the surface of cells.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1100:341-6. DOI:10.1007/978-1-62703-724-2_28
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    ABSTRACT: CD59 overexpression has been shown to confer the resistance of tumors to complement lysis. Complement lysis is one of the two major killing mechanisms of therapeutic anticancer antibodies. This chapter provides a method that allows studying the extent of complement protection of tumors by CD59.
    Methods in molecular biology (Clifton, N.J.) 01/2014; 1100:347-53. DOI:10.1007/978-1-62703-724-2_29
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    ABSTRACT: A career path in academic paediatric medicine is an extremely rewarding one, and while not traditionally considered an academic specialty, it offers a wealth of exciting research opportunities. Developing academic paediatrics is becoming increasingly important, as recently reviewed in the Royal College of Paediatrics and Child Health (RCPCH) Turning the Tide report,1 and developing future leaders in academic paediatrics is a key goal of the academic training pathways. Strategies are being implemented to ensure that the enthusiasm of academic trainees is maintained, and their development into future leaders is secured.2.
    Archives of Disease in Childhood - Education and Practice 12/2013; 99(1). DOI:10.1136/archdischild-2013-304675
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    ABSTRACT: ABO blood group incompatible renal transplantation, using desensitisation procedures, is an effective strategy. Efforts have been made to reduce desensitisation: these are usually applied to all patients indiscriminately. The Guy's Hospital ABO blood group incompatible desensitisation regimen uses a tiered approach, tailoring strategy according to initial antibody titres. 62 ABO blood group incompatible living donor transplant recipients were compared with 167 recipients of blood group compatible living donor renal transplants. There were no statistically significant differences in allograft survival rates at 1 year or 3 years post-transplant, rejection in the first year post-transplant or renal function in the first 3 years post-transplant. There was a higher rate of death in ABO blood group incompatible transplant recipients - this could be associated with differences in age and HLA mismatch between the two groups. 4 ABO blood group incompatible patients experienced Antibody Mediated Rejection (no episode was associated with a rise in ABO blood group antibodies). Of the patients who received no desensitisation, or rituximab alone, none has experienced AMR or experienced allograft loss. Tailoring the use of desensitisation in ABO blood group incompatible renal transplantation according to initial ABO blood group antibody titres led to comparable results to blood group compatible transplantation. This article is protected by copyright. All rights reserved.
    Transplant International 11/2013; 27(2). DOI:10.1111/tri.12234
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    ABSTRACT: Complement is undeniably quintessential for innate immunity by detecting and eliminating infectious microorganisms. Recent work, however, highlights an equally profound impact of complement on the induction and regulation of a wide range of immune cells. In particular, the complement regulator CD46 emerges as a key sensor of immune activation and a vital modulator of adaptive immunity. In this review, we summarize the current knowledge of CD46-mediated signalling events and their functional consequences on immune-competent cells with a specific focus on those in CD4(+) T cells. We will also discuss the promises and challenges that potential therapeutic modulation of CD46 may hold and pose.
    The international journal of biochemistry & cell biology 10/2013; 45(12). DOI:10.1016/j.biocel.2013.09.016
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    ABSTRACT: Autoimmune liver disorders in childhood include autoimmune hepatitis (AIH) and AIH/sclerosing cholangitis overlap syndrome (henceforth referred to as autoimmune sclerosing cholangitis, ASC). These inflammatory liver disorders are characterised histologically by interface hepatitis, biochemically by elevated transaminase levels, and serologically by autoantibodies and increased levels of immunoglobulin G. AIH is particularly aggressive in children and progresses rapidly unless immunosuppressive treatment is started promptly. With appropriate treatment, 80% of patients achieve remission and long-term survival. For non-responders and difficult-to-treat patients, novel and more effective therapeutic approaches are sought. ASC responds to the same treatment used for AIH in regards to parenchymal inflammation, but bile duct disease progresses in about 50% of cases, leading to a worse prognosis and a higher liver transplantation requirement; moreover, it has a high recurrence rate after transplant. Progression of liver disease and recurrence after transplant are more common in patients with associated poorly controlled inflammatory bowel disease. Though the mechanisms underlying the pathogenesis of liver autoimmunity are not fully understood, genetic and environmental factors are likely to be involved. A deeper understanding of the pathogenesis of these conditions will contribute to the development of novel treatments, aimed ultimately at the restoration of tolerance to liver-derived antigens.
    Archives of Disease in Childhood 09/2013; 98(12). DOI:10.1136/archdischild-2013-303848
  • The Journal of pediatrics 08/2013; 163(5). DOI:10.1016/j.jpeds.2013.06.064
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    ABSTRACT: IL-1β is a potent pro-inflammatory cytokine and a therapeutic target in several chronic inflammatory and autoimmune states. Monocytes and macrophages are the major sources of IL-1β. IL-1β production by these cells requires toll-like receptor (TLR) and adenosine triphosphate (ATP)-mediated P2X purinoceptor 7 (P2X7) signals, which together activate the inflammasome. However, how TLR signals and ATP availability are regulated during monocyte activation is unclear and the involvement of another danger signal system has long been proposed. Here, we demonstrate that both lipopolysaccharide (LPS) and the anaphylatoxin C3a, a complement cleavage fragment, are needed for IL-1β production in human macrophages and DCs, while in monocytes, C3a enhanced the secretion of LPS-induced IL-1β. C3a and LPS-stimulated monocytes increased Th17 cell induction in vitro, and human rejecting but not non-rejecting kidney transplant biopsies were characterized by local generation of C3a as well as monocyte and Th17 cell infiltration. Mechanistically, C3a drives IL-1β production in monocytes by controlling the release of intracellular ATP into the extracellular space via regulation of, yet unidentified, ATP-releasing channels in an ERK1/2-dependent fashion. These data define a novel function for complement in inflammasome activation in monocytes and suggest that C3aR-mediated signaling is a vital component of the IL-1β-Th17 axis.
    Blood 07/2013; 122(20). DOI:10.1182/blood-2013-05-502229
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