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Rick M Maizels - One of the best experts on this subject based on the ideXlab platform.

  • characterisation of the secreted apyrase family of Heligmosomoides polygyrus
    International Journal for Parasitology, 2021
    Co-Authors: Rita Berkachy, Rick M Maizels, Yvonne Harcus, Danielle J Smyth, Corinna Schnoeller, Murray E Selkirk, Kleoniki Gounaris
    Abstract:

    Apyrases are a recurrent feature of secretomes from numerous species of parasitic nematodes. Here we characterise the five apyrases secreted by Heligmosomoides polygyrus, a natural parasite of mice and a widely used laboratory model for intestinal nematode infection. All five enzymes are closely related to soluble calcium-activated nucleotidases described in a variety of organisms, and distinct from the CD39 family of ecto-nucleotidases. Expression is maximal in adult worms and restricted to adults and L4s. Recombinant apyrases were produced and purified from Pichia pastoris. The five enzymes showed very similar biochemical properties, with strict calcium dependence and a broad substrate specificity, catalysing the hydrolysis of all nucleoside tri- and diphosphates, with no activity against nucleoside monophosphates. Natural infection of mice provoked very low antibodies to any enzyme, but immunisation with an apyrase cocktail showed partial protection against reinfection, with reduced egg output and parasite recovery. The most likely role for nematode secreted apyrases is hydrolysis of extracellular ATP, which acts as an alarmin for cellular release of IL-33 and initiation of type 2 immunity.

  • demonstration of the anthelmintic potency of marimastat in the Heligmosomoides polygyrus rodent model
    Journal of Parasitology, 2018
    Co-Authors: Elaine Robertson, Rick M Maizels, Yvonne Harcus, Chris J C Johnston, Antony P Page, Malcolm D Walkinshaw, Douglas R Houston
    Abstract:

    ABSTRACT In the course of a structure-based drug discovery program the known anticancer candidate marimastat was uncovered as a potent inhibitor of an enzyme in nematode cuticle biogenesis. It was shown to kill Caenorhabditis elegans, and the sheep parasites Haemonchus contortus and Teladorsagia circumcinta via an entirely novel nematode-specific pathway, specifically by inhibiting cuticle-remodeling enzymes that the parasites require for the developmentally essential molting process. This discovery prompted an investigation of the compound's effect on Heligmosomoides polygyrus parasites in a mouse model of helminth infection. Mice were administered the drug via oral gavage daily from day of infection for a period of 2 wk. A second group received the drug via intra-peritoneal implantation of an osmotic minipump for 4 wk. Control groups were administered identical volumes of water by oral gavage in both cases. Counts of H. polygyrus fecal egg and larval load showed that marimastat effected a consistent and...

  • in vivo nematicidal potential of camel milk on Heligmosomoides polygyrus gastro intestinal nematode of rodents
    Helminthologia, 2018
    Co-Authors: Rick M Maizels, D Alimi, Amel Abidi, E Sebai, Mourad Rekik, Mokhtar Dhibi, Hafidh Akkari
    Abstract:

    Following our previous fi ndings on the in vitro anthelmintic effect of camel milk on Haemonchus contortus, the current study aimed at investigating its in vivo effect. Investigations were carried out using mice infected with Heligmosomoides polygyrus which is a parasite commonly used to test the effi cacy of anthelmintics. Thirty six Swiss white mice of both sexes aged 5 – 6 weeks old, and weighing between 20 and 25 g were orally infected with 0.5 ml dose of 100, 1-week-old H. polygyrus infective larvae (L3 ). After the pre-patent period, infected animals were randomly divided into 6 groups of 6 animals each. The nematicidal effi cacy of camel milk was monitored through faecal egg count reduction (FECR) and total worm count reduction (TWCR). Four doses (8.25; 16.5; 33.0; 66.0 ml/kg body weight (bw)) for fresh camel milk and 22 mg/kg bw for albendazole were studied using a bioassay. Albendazole and 4 % dimethylsulfoxide were included in the protocol as reference drug and placebo, respectively. For all tested doses except 8.25 ml/kg bw, camel milk was effective in vivo against H. polygyrus reducing both faecal egg count and worm count (p < 0.05). The dose 66 ml/kg bw showed the highest nematicidal activity causing a 76.75 % FECR and a 69.62 % TWCR 7 day after initiating the treatment. These results support the possible use of camel milk in the control of gastro-intestinal helminthiasis.

  • novel o linked methylated glycan antigens decorate secreted immunodominant glycoproteins from the intestinal nematode Heligmosomoides polygyrus
    International Journal for Parasitology, 2016
    Co-Authors: James P Hewitson, Linh D Nguyen, Angela Van Diepen, Cornelis H Smit, Carolien A M Koeleman, Henry J Mcsorley, Janice Murray, Rick M Maizels, Cornelis H Hokke
    Abstract:

    Glycan molecules from helminth parasites have been associated with diverse biological functions ranging from interactions with neighbouring host cell populations to down-modulation of specific host immunity. Glycoproteins secreted by the intestinal nematode Heligmosomoides polygyrus are of particular interest as the excretory–secretory products (termed HES) of this parasite contain both heat-labile and heat-stable components with immunomodulatory effects. We used MALDI-TOF-MS and LC–MS/MS to analyse the repertoire of N- and O-linked glycans released from Heligmosomoides polygyrus excretory–secretory products by PNGase A and F, β-elimination and hydrazinolysis revealing a broad range of structures including novel methylhexose- and methylfucose-containing glycans. Monoclonal antibodies to two immunodominant glycans of H. polygyrus, previously designated Glycans A and B, were found to react by glycan array analysis to a methyl-hexose-rich fraction and to a sulphated LacDiNAc (LDN; GalNAcβ1–4GlcNAc) structure, respectively. We also analysed the glycan repertoire of a major glycoprotein in Heligmosomoides polygyrus excretory–secretory products, VAL-2, which contains many glycan structures present in Heligmosomoides polygyrus excretory–secretory products including Glycan A. However, it was found that this set of glycans is not responsible for the heat-stable immunomodulatory properties of Heligmosomoides polygyrus excretory–secretory products, as revealed by the inability of VAL-2 to inhibit allergic lung inflammation. Taken together, these studies reveal that H. polygyrus secretes a diverse range of antigenic glycoconjugates, and provides a framework to explore the biological and immunomodulatory roles they may play within the mammalian host.

  • cultivation of Heligmosomoides polygyrus an immunomodulatory nematode parasite and its secreted products
    Journal of Visualized Experiments, 2015
    Co-Authors: Chris J C Johnston, Henry J Mcsorley, Yvonne Harcus, John R Grainger, Elaine Robertson, Gillian Coakley, Danielle J Smyth, Rick M Maizels
    Abstract:

    Heligmosomoides polygyrus (formerly known as Nematospiroides dubius, and also referred to by some as H. bakeri) is a gastrointestinal helminth that employs multiple immunomodulatory mechanisms to establish chronic infection in mice and closely resembles prevalent human helminth infections. H. polygyrus has been studied extensively in the field of helminth-derived immune regulation and has been found to potently suppress experimental models of allergy and autoimmunity (both with active infection and isolated secreted products). The protocol described in this paper outlines management of the H. polygyrus life cycle for consistent production of L3 larvae, recovery of adult parasites, and collection of their excretory-secretory products (HES).

M Doligalska - One of the best experts on this subject based on the ideXlab platform.

  • the intestinal milieu influences the immunoproteome of male and female Heligmosomoides polygyrus bakeri l4 stage
    Parasitology, 2020
    Co-Authors: Marta Maruszewskacheruiyot, Katarzyna Donskowłysoniewska, Katarzyna Krawczak, Ludmila Szewczak, Ewa Joachimiak, M Doligalska
    Abstract:

    The gastrointestinal nematode Heligmosomoides polygyrus bakeri shows enhanced survival in mice with colitis. As the antibody response plays an important role in antiparasitic immunity, antibodies against male and female L4 H. polygyrus were examined in mice with and without colitis. Levels of specific antibodies in the mucosa and serum were determined by enzyme-linked immunosorbent assay and immunogenic proteins of male and female parasites were identified using 2D electrophoresis and mass spectrometry. The function of identified proteins was explored with Blast2Go. Nematodes in mice with colitis induced higher levels of specific immunoglobulin G (IgG1) and IgA, a lower level of IgE in the small intestine and a higher level of IgE in serum against female L4. Infected mice with colitis recognized 12 proteins in male L4 and 10 in female L4. Most of the recognized proteins from male L4 were intermediate filament proteins, whereas the proteins from female L4 were primarily actins and galectins. Nematodes from mice with colitis were immunogenically different from nematodes from control mice. This phenomenon gives new insights into helminth therapy as well as host-parasite interactions.

  • role of l arginine and cd11b gr 1 cells in immunosuppression induced by Heligmosomoides polygyrus bakeri
    Parasite Immunology, 2020
    Co-Authors: Klaudia Brodaczewska, Katarzyna Donskowłysoniewska, Katarzyna Krawczak, M Doligalska
    Abstract:

    Myeloid-derived suppressor cells (MDSCs) are heterogeneous population of monocyte and granulocyte progenitors that are highly suppressive against T cells. In BALB/c mice infected with a nematode Heligmosomoides polygyrus bakeri, we studied the dynamics of MDSCs, identified as CD11b+Gr-1+, induction in different tissues along with the development of parasite infection. We observed that MDSC-like cells are induced both by larvae and adult stages of H polygyrus bakeri. Gr-1+ cells of suppressive phenotype are recruited in the bone marrow, peripheral blood and peritoneal cavity during histotropic phase of infection and are present at that time in the intestine wall, where worms reside. Later, during intestinal phase, suppressive Gr-1+ cells increased in mesenteric lymph nodes and the spleen. l-arginine metabolism was important for the protective immunity, and parasite-induced Gr-1+ cells showed elevated arginase-1 and iNOS expression. Inhibition of arginase-1 and l-arginine administration caused reduced level of infection that coincided with weaker suppressive phenotype of Gr-1+ cells. We identified that l-arginine pathway activation and induction of MDSC-like cells characterize immunosuppressive state during H polygyrus bakeri infection in mice. Our findings confirm the role of MDSCs in parasitic infections and point l-arginine pathway as a potential target for immunomodulation during nematode infections.

  • l4 stage Heligmosomoides polygyrus prevents the maturation of dendritic jaws ii cells
    Experimental Parasitology, 2019
    Co-Authors: Marta Maruszewskacheruiyot, Katarzyna Donskowłysoniewska, Katarzyna Krawczak, Karolina Piechna, M Doligalska
    Abstract:

    Helminths and their products are strong candidates for the treatment of autoimmunological disorders and allergies. Being a key population of antigen-presenting cells, dendritic cells play a crucial role in the therapeutic potential of worms. The study compares the effects of live pre-male and pre-female L4 stage Heligmosomoides polygyrus administration on the maturation and activation of the JAWS II line of immature dendritic cells. On stimulation with L4 stage H. polygyrus, JAWS II cells acquire semi-mature status and induce Th2 and regulatory responses in vitro. The strongest immunosuppressive effect on JAWS II cells was observed following stimulation with both sexes of nematodes together; this was manifested as immature dendritic cell morphology, proliferation inhibition, cell cycle change, decreased translocation of NF-κB into the nucleus, and lower expression of surface cellular costimulatory molecules CD80, CD86 and MHC I. However, greater production of proinflammatory (IL-12p70, TNF-α, IL-6) and Th2 response-promoting cytokines (IL-4) was observed by JAWS II following exposure to both sexes compared to male or female larvae alone. Sex had no influence on the viability, apoptosis process or endocytosis abilities of the JAWS II cell line. The findings indicate that the presence of only a single sex of the parasite influences a developed response, resulting in reduced proinflammatory and an antiparasitic reaction.

  • changes in Heligmosomoides polygyrus glycoprotein pattern by saponins impact the balb c mice immune response
    Experimental Parasitology, 2013
    Co-Authors: M Doligalska, Marzena Laskowska, Katarzyna Donskowłysoniewska, Kinga Joźwicka, Cezary Pączkowski, Wirginia Janiszowska
    Abstract:

    Abstract Saponins of marigold ( Calendula officinalis), in particular derivatives of 3-O-monoglucuronide of oleanolic acid, are able to reduce infectivity of Heligmosomoides polygyrus in mice. The purpose of this study was to understand the immune activation provoked by third-stage larvae exposed to marigold glucuronides. We also examined the pattern of glycosylation of larval antigens which appeared to be crucial for induction of cytokine production in BALB/c mice; higher concentrations of IL-6, IFN-γ, IL-10 and TNF-α were observed in serum or intestine one week post infection. Three weeks later, in the chronic phase of infection, cells in culture were able to produce IL-6, IFN-γ, TNF-α and IL-17. Restimulation of cells with H. polygyrus antigen resulted in reduced production of IL-6, and TNF-α. The pattern of cytokine production co-existed with reduced expression of terminal glucose, α-linked mannose, N-acetyl-galactosamine, β-galactose, N-acetyl-glucosamine and α-fucose in several protein bands. Galactose, as a new terminal carbohydrate residue appeared in 20–24 kDa protein bands. The number of immunogenic epitopes in parasitic antigens was reduced; only three protein bands of 56, 26 and 12 kDa were recognized by IgG1. These studies provide a model system to find the glycosylated molecules expressed on nematodes that improve establishment and survival and characterize cytokine production in mice infected with larvae exposed to saponin. Identification of these molecules is the first step in the recognition of key antigenic epitopes able to induce protective or tolerogenic immune responses.

  • colitis promotes adaptation of an intestinal nematode a Heligmosomoides polygyrus mouse model system
    PLOS ONE, 2013
    Co-Authors: Katarzyna Donskowłysoniewska, Klaudia Brodaczewska, Katarzyna Krawczak, Justyna Bien, M Doligalska
    Abstract:

    The precise mechanism of the very effective therapeutic effect of gastrointestinal nematodes on some autoimmune diseases is not clearly understood and is currently being intensively investigated. Treatment with living helminths has been initiated to reverse intestinal immune-mediated diseases in humans. However, little attention has been paid to the phenotype of nematodes in the IBD-affected gut and the consequences of nematode adaptation. In the present study, exposure of Heligmosomoides polygyrus larvae to the changed cytokine milieu of the intestine during colitis reduced inflammation in an experimental model of dextran sulphate sodium (DSS)- induced colitis, but increased nematode establishment in the moderate-responder BALB/c mouse strain. We used mass spectrometry in combination with two-dimensional Western blotting to determine changes in protein expression and changes in nematode antigens recognized by IgG1 in mice with colitis. We show that nematode larvae immunogenicity is changed by colitis as soon as 6 days post-infection; IgG1 did not recognize highly conserved proteins Lev-11 (isoform 1 of tropomyosin α1 chain), actin-4 isoform or FTT-2 isoform a (14-3-3 family) protein. These results indicate that changes in the small intestine provoked by colitis directly influence the nematode proteome. The unrecognized proteins seem to be key antigenic epitopes able to induce protective immune responses. The proteome changes were associated with weak immune recognition and increased larval adaptation and worm growth, altered localization in the intestine and increased survival of males but reduced worm fecundity. In this report, the mechanisms influencing nematode survival and the consequences of changed immunogenicity that reflect the immune response at the site colonized by the parasite in mice with colitis are described. The results are relevant to the use of live parasites to ameliorate IBD.

Mary M Stevenson - One of the best experts on this subject based on the ideXlab platform.

  • production and analysis of immunomodulatory excretory secretory products from the mouse gastrointestinal nematode Heligmosomoides polygyrus bakeri
    Nature Protocols, 2014
    Co-Authors: Rajesh Valanparambil, Mariela Segura, Mifong Tam, Armando Jardim, Timothy G Geary, Mary M Stevenson
    Abstract:

    This protocol describes how to maintain the gastrointestinal nematode Heligmosomoides polygyrus bakeri and generate excretory-secretory products for identification, cloning, and immunological characterization of the modulatory molecules.

  • Production and analysis of immunomodulatory excretory-secretory products from the mouse gastrointestinal nematode Heligmosomoides polygyrus bakeri
    Nature Protocols, 2014
    Co-Authors: Rajesh Valanparambil, Mariela Segura, Armando Jardim, Timothy G Geary, Mary M Stevenson
    Abstract:

    Heligmosomoides polygyrus bakeri (Hpb) infection in mice is a convenient model for studying the pathophysiology and immunology of gastrointestinal (GI) helminth infection. Hpb infection suppresses immune responses to bystander antigens and unrelated pathogens, and it slows the progression and modifies the outcome of immune-mediated diseases. Hpb-derived excretory-secretory (ES) products potently modulate CD4^+ helper T cell (T_H) responses by inducing regulatory T cells, tolerogenic dendritic cells (DCs) and immunoregulatory cytokines. This observation has spiked interest in identifying the immunomodulatory molecules, especially proteins, in ES products from Hpb and other GI nematodes for development as novel therapies to treat individuals with immune-mediated diseases, such as inflammatory bowel diseases (IBDs). In this protocol, we describe how to (i) maintain Hpb in the laboratory for experimental infections, (ii) collect adult worms from infected mice to generate ES products and (iii) evaluate the modulatory effects of ES products on toll-like receptor (TLR) ligand–induced maturation of CD11c^+ DCs. The three major sections of the PROCEDURE can be used independently, and they require ∼6, 10 and 27 h, respectively. Although other methods use a modified Baermann apparatus to collect Hpb adult worms, we describe a method that involves dissection of adult worms from intestinal tissue. The protocol will be useful to investigators studying the host-parasite interface and identifying and analyzing helminth-derived molecules with therapeutic potential. This protocol describes how to maintain the gastrointestinal nematode Heligmosomoides polygyrus bakeri and generate excretory-secretory products for identification, cloning, and immunological characterization of the modulatory molecules.

  • dietary protein and zinc restrictions independently modify a Heligmosomoides polygyrus nematoda infection in mice
    Parasitology, 1998
    Co-Authors: M Boulay, Marilyn E Scott, Mary M Stevenson, S L Conly, Kristine G Koski
    Abstract:

    The effects of dietary protein and zinc restrictions on Heligmosomoides polygyrus were compared following primary and challenge infection in female BALB/c mice fed either control (24%), marginal (7%) or low (3%) protein combined with either high or low zinc (60 or 3 mg Zn/kg diet). Dietary protein restriction (3%) resulted in significantly lower body weight gain. As well, blood urea nitrogen (BUN) significantly decreased with decreasing dietary protein level. However, neither plasma albumin concentration nor relative thymus or spleen weights were reduced. Marginal zinc deficiency was confirmed by significantly lower tibia and liver zinc concentration, but food intake, body weight gain, relative thymus and spleen weights, and alkaline phosphatase activity were not altered. On day 29 post-primary infection, worm burdens were significantly higher in mice fed either marginal or low protein and in mice fed a low zinc diet, while parasite egg output was significantly higher in mice fed both low protein and low zinc diets. Immune status was compromised in mice fed low protein (significantly lower serum IgG1 and lower eosinophilia), and in mice fed low zinc diet (significantly lower eosinophilia). Early in the infection, IgE titres were elevated in mice fed low protein or low zinc, but IgE titres declined to levels lower than the control diet groups after 14–21 days. On day 29 post-challenge infection, worm burdens and parasite egg output were significantly higher in mice fed low protein, whereas the other groups had expelled almost all parasites. Dietary restriction had no effect on serum IgE. Significantly reduced serum IgG1 titres and eosinophilia in mice fed 3% protein supported the view that low dietary protein but not low zinc increased host susceptibility to H. polygyrus by compromising host immune function following reinfection in immunized mice.

  • zinc deficiency impairs t cell function in mice with primary infection of Heligmosomoides polygyrus nematoda
    Parasite Immunology, 1994
    Co-Authors: Hai Ning Shi, Marilyn E Scott, Mary M Stevenson, Kristine G Koski
    Abstract:

    SUMMARY This study was designed to determine whether severe zinc deficiency would prolong the course of a primary Heligmosomoides polygyrus infection in mice, and whether this could be related to impaired T cell function. Female BALB/c mice were fed a zinc-sufficient (Zn+; 60 mg/kg), a zinc-deficient (Zn-; 0.75 mg/kg) or an energy restricted (PF; 60 mg zinc/kg) diet. After four weeks, some mice in each dietary group were given a primary infection with 100 larvae; nutritional, parasitological and immunological parameters were assayed over the following five weeks. Liver zinc concentrations were significantly reduced in Zn- mice compared with Zn+ mice. In certain cases, PF mice also had reduced liver zinc concentrations, showing the negative effects of restricted food intake on zinc status. Zinc deficiency prolonged the course of a primary infection, with the effects being most evident five weeks post-infection when Zn+ mice had only 40% as many worms as Zn- mice. Parasite infection induced strong immunological responses in Zn+ mice in contrast to Zn- mice. The reduced production of IL-4 and IFN-γ, the reduced peripheral eosinophilia and reduced serum levels of IgE and IgG1 in Zn- mice were attributed to the zinc deficiency, whereas the reduced delayed type hypersensitivity response to parasite antigen and reduced production of IL-5 were in certain instances attributed to reduced energy intake rather than zinc deficiency. These results show that zinc deficiency significantly impairs functions normally attributed to both Th1 and Th2 cell populations, and that these alterations are associated with elevated worm numbers in zinc-deficient mice.

Jerzy M Behnke - One of the best experts on this subject based on the ideXlab platform.

  • assessment of the anthelmintic effect of natural plant cysteine proteinases against the gastrointestinal nematode Heligmosomoides polygyrus in vitro
    Parasitology, 2005
    Co-Authors: Gillian Stepek, David J Buttle, Ian R Duce, Ann Lowe, Jerzy M Behnke
    Abstract:

    We examined the mechanism of action and compared the anthelmintic efficacy of cysteine proteinases from papaya, pineapple, fig, kiwi fruit and Egyptian milkweed in vitro using the rodent gastrointestinal nematode Heligmosomoides polygyrus. Within a 2 h incubation period, all the cysteine proteinases, with the exception of the kiwi fruit extract, caused marked damage to the cuticle of H. polygyrus adult male and female worms, reflected in the loss of surface cuticular layers. Efficacy was comparable for both sexes of worms, was dependent on the presence of cysteine and was completely inhibited by the cysteine proteinase inhibitor, E-64. LD50 values indicated that the purified proteinases were more efficacious than the proteinases in the crude latex, with purified ficin, papain, chymopapain, Egyptian milkweed latex extract and pineapple fruit extract, containing fruit bromelain, having the most potent effect. The mechanism of action of these plant enzymes (i.e. an attack on the protective cuticle of the worm) suggests that resistance would be slow to develop in the field. The efficacy and mode of action make plant cysteine proteinases potential candidates for a novel class of anthelmintics urgently required for the treatment of humans and domestic livestock.

  • the relationship between circulating and intestinal Heligmosomoides polygyrus specific igg1 and iga and resistance to primary infection
    Parasite Immunology, 1999
    Co-Authors: Anne Bensmith, F N Wahid, David A Lammas, Jerzy M Behnke
    Abstract:

    SUMMARY Specific serum and intestinal immunoglobulin (Ig)G 1 and IgA responses to Heligmosomoides polygyrus were measured in a panel of seven inbred mouse strains which exhibit ‘rapid’ ( 25 weeks, C57BL/10 and CBA) resolution of primary infections. Mice with ‘rapid’, ‘fast’ or ‘intermediate’ response phenotypes produced greater serum and intestinal antibody responses than those with ‘slow’ phenotypes. The F1 hybrids ((SWR〈 SJL)F1) of two ‘fast’ responder strains showed the earliest antibody response with maximum titres evident within 6 weeks of infection. There was a negative correlation between the serum IgG 1 responses and worm burdens in individual mice within a number of mouse strains, and also between serum IgG 1 and IgA responses and worm burdens in the ‘rapid’ ((SWR〈 SJL)F1) responder strain. The presence of IgG 1 in the gut was found to be due to local secretion rather than plasma leakage. Using Western immunoblotting, serum IgG1 from ‘rapid’ and ‘fast’ responder but not ‘slow’ responder mice was found to react with low molecular weight antigens (16‐18 kDa) in adult worm excretory/ secretory products.

  • glutathione s transferases from the gastrointestinal nematode Heligmosomoides polygyrus and mammalian liver compared
    Comparative Biochemistry and Physiology B, 1994
    Co-Authors: Peter M. Brophy, Jerzy M Behnke, Anne Bensmith, Alan Brown, D I Pritchard
    Abstract:

    Glutathione S-transferases have been partially characterised from the gastrointestinal nematode Heligmosomoides polygyrus. Two major subunit families were purified (24 and 23 kDa) with N-terminal homology to the mammalian Alpha family. Four dimeric forms of GST were purified from the nematode by glutathione-affinity chromatography, two major enzymes (pI 8.1, 5.0) and two minor forms (pI 5.8, 5.3). The purified GST pool could neutralize model and lipid peroxides via peroxidase activity but not peroxidation derived reactive carbonyls via glutathione transferase activity. Antisera raised to the pooled nematode GSTs appeared to recognize other Strongylida GSTs more strongly on Western blotting compared to mammalian GSTs.

  • immunological relationships during primary infection with Heligmosomoides polygyrus th2 cytokines and primary response phenotype
    Parasitology, 1994
    Co-Authors: F N Wahid, Jerzy M Behnke, Richard K Grencis, Kathryn J Else, Anne Bensmith
    Abstract:

    The primary immune response to infection with Heligmosomoides polygyrus was studied in mice differing in response phenotype (fast-SWR, intermediate-NIH, slow-CBA). Marked IgG1 and IgE but not IgG2a antibody responses were detected in infected mice and the former were more intense in fast compared with slow responder strains. Mastocytosis, MMCP-1, and the secretion of cytokines by mesenteric lymph node cells, following stimulation in vitro by Con A, were also more intense initially in SWR mice. Secretion of IL-4 declined in all strains by the 4th week of infection, irrespective of response phenotype. IL-10 was only produced briefly by SWR mice. However, the temporal patterns of secretion of IL-3 and IL-9 clearly distinguished fast from slow responder phenotypes. Following initial intense secretion of IL-3, production declined in all strains but in the 5-6th weeks enhanced secretion was evident in SWR and NIH mice and was sustained until week 10 p.i. In contrast, CBA mice never recovered from the initial down-regulation in weeks 3-4 and secretion declined to background levels by week 6 p.i. despite the continued presence of adult worms. Temporal changes in the secretion of IL-9 were very similar: secretion declined in CBA mice by week 6 p.i., whilst SWR and NIH mice continued to secrete high amounts. We suggest that fast and slow responder mice differ not only in their initial responsiveness to parasite antigens but also in their ability to sustain a Th2 response to the parasite and we propose that the latter is in part determined by their different susceptibilities to parasite-mediated immunomodulation. Only the fast responder strains can sustain a Th2 response of sufficient intensity to facilitate expulsion of adult worms.

  • immunological relationships during primary infection with Heligmosomoides polygyrus nematospiroides dubius parasite specific igg1 antibody responses and primary response phenotype
    Parasite Immunology, 1993
    Co-Authors: F N Wahid, Jerzy M Behnke
    Abstract:

    SUMMARY IgGl antibody responses to Heligmosomoides polygyrus were measured in eight mouse strains supporting acute ( 25 weeks, C57BLI0, CBA, C3H, AKR) primary infections. Mice supporting acute or intermediate infections produced more intense antibody responses and total serum IgGl concentrations were higher than in mice tolerating chronic infections. Positive correlations across mouse strains between the intensity of the antibody response and the percentage loss of worms in weeks 6 and I0 were established. No correlation was found hetween the response within mouse strains and loss of worms by individual mice. Heavy infections gave marginallv higher antibody titres than low intensity injkctions, but few sign$cant diflerences were detected and it was concluded that infection intensity did not markedly influenee the magnitude of the antibody response. Male and female mice responded similarly despite the earlier loss of worms,from females. No association was,found between the primary response phenotype and recognition of particular antigens in Western blot analysis, nor did intensity of infection or host gender a$ect recognition. The possibility that immunomodulatory properties qf adult worms may have hud a direrential influence on ability of strains of contrasting response phenotype to mount IgGl responses wus discussed.

Joel V Weinstock - One of the best experts on this subject based on the ideXlab platform.

  • Heligmosomoides polygyrus bakeri infection activates colonic foxp3 t cells enhancing their capacity to prevent colitis
    Journal of Immunology, 2013
    Co-Authors: Long Hang, Tommy Setiawan, Arthur M Blum, Korynn Stoyanoff, Joseph P Urban, Joel V Weinstock
    Abstract:

    Helminthic infections protect mice from colitis in murine models of inflammatory bowel disease and also may protect people. Helminths like Heligmosomoides polygyrus bakeri can induce regulatory T cells (Treg). Experiments explored whether H. polygyrus bakeri infection could protect mice from colitis through activation of colonic Treg and examined mechanisms of action. We showed that H. polygyrus bakeri infection increased the number of T cells expressing Foxp3 in the colon. More importantly, Foxp3+/IL-10− and Foxp3+/IL-10+ T cell subsets isolated from the colon of H. polygyrus bakeri–infected mice prevented colitis when adoptively transferred into a murine model of inflammatory bowel disease, whereas Treg from uninfected mice could not provide protection. Only the transferred colonic Foxp3+/IL-10− T cells from H. polygyrus bakeri–infected mice readily accumulated in the colon and mesenteric lymph nodes of recipient mice, and they reconstituted the Foxp3+/IL-10− and Foxp3+/IL-10+ T cell subsets. However, transferred Foxp3+/IL-10+ T cells disappeared. IL-10 expression by Foxp3+ T cells was necessary for colitis prevention. Thus, H. polygyrus bakeri infection activates colonic Foxp3+ T cells, making them highly regulatory. The Foxp3+ T cells that fail to express IL-10 may be critical for populating the colon with the Foxp3+/IL-10+ T cells, which are required to control colitis.

  • Heligmosomoides polygyrus abrogates antigen specific gut injury in a murine model of inflammatory bowel disease
    Inflammatory Bowel Diseases, 2012
    Co-Authors: John Leung, Tommy Setiawan, Arthur M Blum, Long Hang, Korynn Stoyanoff, Joel V Weinstock
    Abstract:

    Background: Developing countries have a low incidence of inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections and other alterations in intestinal flora and fauna. Helminth infections prevent colitis in various murine models of IBD. IBD may be driven by an aberrant immune response to luminal antigen(s). Methods: We developed a murine model of IBD in which gut injury was induced by a specific antigen to better simulate the IBD disease process and to determine if helminth infections could abolish gut injury induced by an orally administered antigen. The model features pan-enterocolitis triggered by feeding ovalbumin (OVA). Results: The intestinal inflammation is antigen-specific and generates interleukin (IL)-17 and interferon-gamma (IFN-γ), but not IL-4. Full expression of the disease required T cells with defective capacity to make IL-10 and treatment with a noninjurious, low dose of a nonsteroidal antiinflammatory drug. Exposure to Heligmosomoides polygyrus abrogated this antigen-induced gut injury. H. polygyrus colonization induced Foxp3+ T regulatory cells (Tregs) and mucosal production of IL-10 from non-T cells. Lamina propria mononuclear cells from H. polygyrus-infected mice released less IL-17 and IFN-γ constitutively and when stimulated with OVA or anti-CD3/CD28 monoclonal antibodies. Conclusions: We developed a murine IBD model featuring antigen-specific enterocolitis and demonstrate for the first time that gut inflammation induced by an antigen could be abrogated by H. polygyrus infection. Protection was associated with suppressed IL-17 and IFN-γ production, induction of Foxp3+ Tregs, and elevated secretion of non-T-cell-derived IL-10, all of which could be part of the protective processes. (Inflamm Bowel Dis 2012)

  • alteration of the murine gut microbiota during infection with the parasitic helminth Heligmosomoides polygyrus
    Inflammatory Bowel Diseases, 2010
    Co-Authors: Seth T Walk, Arthur M Blum, Joel V Weinstock, Sarah A Ewing, Vincent B Young
    Abstract:

    In a murine model of inflammatory bowel disease (IBD), treatment of colitis in IL-10 gene deficient mice with the parasitic helminth, Heligmosomoides polygyrus, ameliorates colonic inflammation. The cellular and molecular mechanisms driving this therapeutic host response are being studied vigorously. One proposed mechanism is that H. polygyrus infection favors the outgrowth or suppression of certain bacteria, which in turn help modulate host immunity. To begin to address this hypothesis, we quantified the effect of H. polygyrus treatment on the composition of the gastrointestinal (GI) tract microbiota in the absence of inflammation, using wild-type C57BL/6 mice. Here, we present evidence that a significant shift in the abundance and relative distribution of bacterial species in the ileum of mice is associated with H. polygyrus infection. Members of the bacterial family, Lactobacillaceae, significantly increased in abundance in the ileum of infected mice reproducibly in two independent experiments despite having different microbiotas present at the outset of each experiment. These data support the concept that helminth infection shifts the composition of intestinal bacteria. The clinical consequences of these shifts in intestinal flora are yet to be explored.

  • Heligmosomoides polygyrus infection can inhibit colitis through direct interaction with innate immunity
    Journal of Immunology, 2010
    Co-Authors: Long Hang, Joseph F. Urban, Tommy Setiawan, Arthur M Blum, Korynn Stoyanoff, Seiji Arihiro, Hanschristian Reinecker, Joel V Weinstock
    Abstract:

    Less developed countries have a low incidence of immunological diseases like inflammatory bowel disease (IBD), perhaps prevented by the high prevalence of helminth infections in their populations. In the Rag IL-10(-/-) T cell transfer model of colitis, Heligmosomoides polygyrus, an intestinal helminth, prevents and reverses intestinal inflammation. This model of colitis was used to explore the importance of innate immunity in H. polygyrus protection from IBD. Rag mice briefly exposed to H. polygyrus before reconstitution with IL-10(-/-) colitogenic T cells are protected from colitis. Exposure to H. polygyrus before introduction of IL-10(-/-) and OT2 T cells reduced the capacity of the intestinal mucosa to make IFN-gamma and IL-17 after either anti-CD3 mAb or OVA stimulation. This depressed cytokine response was evident even in the absence of colitis, suggesting that the downmodulation in proinflammatory cytokine secretion was not just secondary to improvement in intestinal inflammation. Following H. polygyrus infection, dendritic cells (DCs) from the lamina propria of Rag mice displayed decreased expression of CD80 and CD86, and heightened expression of plasmacytoid dendritic cell Ag-1 and CD40. They were also less responsive to lamina proprias, producing less IL-12p40 and IL-10. Also diminished was their capacity to present OVA to OT2 T cells. These experiments infer that H. polygyrus does not require direct interactions with T or B cells to render animals resistant to colitis. DCs have an important role in driving both murine and human IBD. Data suggest that phenotypic alternations in mucosal DC function are part of the regulatory process.

  • Heligmosomoides polygyrus promotes regulatory t cell cytokine production in the murine normal distal intestine
    Infection and Immunity, 2007
    Co-Authors: Tommy Setiawan, Joseph F. Urban, Ahmed Metwali, Arthur M Blum, David E Elliott, Nedim M Ince, Joel V Weinstock
    Abstract:

    Helminths down-regulate inflammation and may prevent development of several autoimmune illnesses, such as inflammatory bowel disease. We determined if exposure to the duodenal helminth Heligmosomoides polygyrus establishes cytokine pathways in the distal intestine that may protect from intestinal inflammation. Mice received 200 H. polygyrus larvae and were studied 2 weeks later. Lamina propria mononuclear cells (LPMC) were isolated from the terminal ileum for analysis and in vitro experiments. Mice with H. polygyrus were resistant to trinitrobenzenesulfonic acid (TNBS)-induced colitis, a Th1 cytokine-dependent inflammation. Heligmosomoides polygyrus did not change the normal microscopic appearance of the terminal ileum and colon and minimally affected LPMC composition. However, colonization altered LPMC cytokine profiles, blocking gamma interferon (IFN-γ) and interleukin 12 (IL-12) p40 release but promoting IL-4, IL-5, IL-13, and IL-10 secretion. IL-10 blockade in vitro with anti-IL-10 receptor (IL-10R) monoclonal antibody restored LPMC IFN-γ and IL-12 p40 secretion. IL-10 blockade in vivo worsened TNBS colitis in H. polygyrus-colonized mice. Lamina propria CD4+ T cells isolated from colonized mice inhibited IFN-γ production by splenic T cells from worm-free mice. This inhibition did not require cell contact and was dependent on IL-10. Heligmosomoides polygyrus colonization inhibits Th1 and promotes Th2 and regulatory cytokine production in distant intestinal regions without changing histology or LPMC composition. IL-10 is particularly important for limiting the Th1 response. The T-cell origin of these cytokines demonstrates mucosal regulatory T-cell induction.