Balic, A., Harcus, Y., Holland, M.J. & Maizels, R.M. Selective maturation of dendritic cells by Nippostrongylus brasiliensis-secreted proteins drives Th2 immune responses. Eur. J. Immunol. 34, 3047-3059

Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, UK.
European Journal of Immunology (Impact Factor: 4.03). 12/2004; 34(11):3047-59. DOI: 10.1002/eji.200425167
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Helminth infections at mucosal and tissue sites strongly polarize towards Th2 immune responses, following pathways which have yet to be elucidated. We investigated whether dendritic cells (DC) exposed to gastrointestinal nematodes induce Th2 differentiation and, if so, whether this outcome reflects the absence of DC activation (the default hypothesis). We studied secreted proteins from the parasite Nippostrongylus brasiliensis, which induce Th2 development in vivo without live infection. Murine bone marrow-derived DC pulsed with N. brasiliensis excretory/secretory antigen (NES) can, on transfer to naive recipients, prime mice for Th2 responsiveness. Heat inactivation of NES abolishes both its ability to drive Th2 responses in vivo and its capacity to stimulate DC for Th2 induction. NES, but not heat-inactivated NES, up-regulates DC maturation markers associated with Th2 promotion (CD86 and OX40L), with little change to CD80 and MHC class II. Moreover, DC exposed to NES readily produce IL-6 and IL-12p40, but not IL-12p70. LPS induced high IL-12p70 levels, except in DC that had been pre-incubated with NES. These data contradict the default hypothesis, demonstrating that a helminth product (NES) actively matures DC, selectively up-regulating CD86 and OX40L together with IL-6 production, while blocking IL-12p70 responsiveness in a manner consistent with Th2 generation in vivo.

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Available from: Martin J Holland, Oct 03, 2015
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    • "In this context, what stands out is the observation that pLL on its own induces, in vitro and in vivo, the upregulation of CD86. Selective upregulation of CD86 among major costimulatory molecules was also reported in DCs exposed to the excretory-secretory products of the nematode Nippostrongylus brasiliensis (49). However, in contrast to our experimental system, this was accompanied by secretion of IL-6 and IL-12/23p40, suggesting that exposure to the N. brasiliensis extract caused some NF-κB activation. "
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    ABSTRACT: The larval stage of the cestode parasite Echinococcus granulosus causes hydatid disease in humans and livestock. This infection is characterized by the growth, in internal organ parenchymae, of fluid-filled structures (hydatids) that elicit surprisingly little inflammation in spite of their massive size and persistence. Hydatids are protected by a mm-thick layer of mucin-based extracellular matrix, termed laminated layer (LL), which is thought to be a major factor determining the host response in this infection. Host cells can interact both with the LL surface and with materials that are shed from it to allow parasite growth. In this work, we analyzed the response of dendritic cells (DCs) to microscopic pieces of the native mucin-based gel of the LL (pLL). In vitro, this material induced an unusual activation state characterized by up-regulation of CD86 without concomitant up-regulation of CD40 or secretion of cytokines (IL-12, IL-10, TNF-α, IL-6). When added together with TLR agonists, pLL potentiated CD86 up-regulation and IL-10 secretion, while inhibiting CD40 up-regulation and IL-12 secretion. In vivo, pLL also caused up-regulation of CD86 and inhibited CD40 up-regulation in DCs. Contrary to expectation, oxidation of the mucin glycans in pLL with periodate did not abrogate the effects on cells. Reduction of disulphide bonds, which are known to be important for LL structure, strongly diminished the impact of pLL on DCs, without altering the particulate nature of the material. In summary, DCs respond to the LL mucin meshwork with a "semi-mature" activation phenotype, both in vitro and in vivo.
    Infection and Immunity 05/2014; 82(8). DOI:10.1128/IAI.01959-14 · 3.73 Impact Factor
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    • "Ruyssers et al. [25] and Cancado et al. [26] recently demonstrated the therapeutic potential of excretory/secretory (ES) products from adult hookworms, Ancylostoma caninum and A. ceylanicum, on experimental colitis in mice, predominantly through the down-regulation of Th1 and Th17 cytokines. Although helminthic ES products could directly modulate dendritic cells (DC), suppress the expression of co-stimulatory MHCII and produce anti-inflammatory cytokines [20], modulation of the immune system by ES products derived from different helminth species or developmental stages may act differently [27], [28], [29], [30]. T. spiralis is one of the most widespread zoonotic parasitic nematodes in the world. "
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    ABSTRACT: Many evidences show the inverse correlation between helminth infection and allergic or autoimmune diseases. Identification and characterization of the active helminth-derived products responsible for the beneficial effects on allergic or inflammatory diseases will provide another feasible approach to treat these diseases. Colitis was induced in C57BL/6 mice by giving 3% DSS orally for 7 days. During this period, the mice were treated daily with the excretory/secretory products from T. spiralis adult worms (AES) intraperitoneally. The severity of colitis was monitored by measuring body weight, stool consistency or bleeding, colon length and inflammation. To determine the T. spiralis AES product-induced immunological response, Th1, Th2, Th17 and regulatory cytokine profiles were measured in lymphocytes isolated from colon, mesenteric lymph nodes (MLN), and the spleen of treated mice. The CD4+ CD25+ FOXP3+ regulatory T cells (Tregs) were also measured in the spleens and MLN of treated mice. Mice treated with AES significantly ameliorated the severity of the DSS-induced colitis indicated by the reduced disease manifestations, improved macroscopic and microscopic inflammation correlated with the up-regulation of Treg response (increased regulatory cytokines IL-10, TGF-beta and regulatory T cells) and down-regulation of pro-inflammatory cytokines (IFN-gamma, IL-6 and IL-17) in the spleens, MLN and colon of treated mice. Our results provide direct evidences that T. spiralis AES have a therapeutic potential for alleviating inflammatory colitis in mice. This effect is possibly mediated by the immunomodulation of regulatory T cells to produce regulatory and anti-inflammatory cytokines and inhibit pro-inflammatory cytokines.
    PLoS ONE 05/2014; 9(5):e96454. DOI:10.1371/journal.pone.0096454 · 3.23 Impact Factor
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    • "Future work should give valuable insights into the mechanisms of suppression of Th2 responses against both parasites and bystander antigens both at the level of Th2 induction (by administering parasite products with the OVA sensitisation), and established anti-parasite Th2 responses (by administering parasite products at OVA-airway challenge). A possibility that should be considered is whether helminth molecules induce a competing Th2 response, as many parasite products themselves induce potent Th2 responses in vivo (Balic et al., 2004; Dowling et al., 2011; Zaccone et al., 2011) and in the case of administration of NES products, an allergic-type response developed to the ES antigens themselves (Trujillo-Vargas et al., 2007). "
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    ABSTRACT: Epidemiological and interventional human studies, as well as experiments in animal models, strongly indicate that helminth parasitic infections can confer protection from immune dysregulatory diseases such as allergy, autoimmunity and colitis. Here, we review the immunological pathways that helminths exploit to downregulate immune responses, both against bystander specificities such as allergens and against antigens from the parasites themselves. In particular, we focus on a highly informative laboratory system, the mouse intestinal nematode, Heligmosomoides polygyrus, as a tractable model of host-parasite interaction at the cellular and molecular levels. Analysis of the molecules released in vitro (as excretory-secretory products) and their cellular targets is identifying individual parasite molecules and gene families implicated in immunomodulation, and which hold potential for future human therapy of immunopathological conditions.
    International journal for parasitology 01/2013; 43(3-4). DOI:10.1016/j.ijpara.2012.11.011 · 3.87 Impact Factor
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