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• W2129589060 abstract "Substantial data show that infection with helminth parasites ameliorates colitis; however, oxazolone-induced colitis is exaggerated in mice infected with the tapeworm, Hymenolepis diminuta. We tested the hypothesis that the IL-5 response to helminth infection enhances the severity of oxazolone-induced colitis. Mice were infected with H. diminuta and 8 days later were treated with oxazolone ± anti–IL-5 antibodies. Colitis was assessed 72 hours postoxazolone treatment by disease activity scores, myeloperoxidase activity, and histopathology. Other mice received injections of a replication-deficient adenovirus that carried the IL-5 (Ad.IL-5) gene or a control adenovirus (Ad.delete) ± oxazolone. The effect of H. diminuta+oxazolone in CCL11/CCL22 (eotaxin-1 and 2) knockout (KO) mice was determined. Helminth infection and Ad.IL-5 treatment increased IL-5 and eosinophil numbers. In vivo neutralization of IL-5 significantly reduced the severity of colitis in H. diminuta+oxazolone-treated mice, and H. diminuta did not exaggerate oxazolone-induced colitis in CCL11/CCL22 KO mice. Mice receiving Ad.IL-5 only had no colitis, while oxazolone-induced colitis was more severe in animals cotreated with Ad.IL-5 (Ad.delete + oxazolone was not significantly different from oxazolone only). Thus, while there is much to be gleaned about antiinflammatory mechanisms from rodent-helminth model systems, these data illustrate the caveat that infection with helminth parasites as a therapy could be contraindicated in patients with eosinophilia or elevated IL-5 unless coupled to appropriate measures to block IL-5 and/or eosinophil activity. Substantial data show that infection with helminth parasites ameliorates colitis; however, oxazolone-induced colitis is exaggerated in mice infected with the tapeworm, Hymenolepis diminuta. We tested the hypothesis that the IL-5 response to helminth infection enhances the severity of oxazolone-induced colitis. Mice were infected with H. diminuta and 8 days later were treated with oxazolone ± anti–IL-5 antibodies. Colitis was assessed 72 hours postoxazolone treatment by disease activity scores, myeloperoxidase activity, and histopathology. Other mice received injections of a replication-deficient adenovirus that carried the IL-5 (Ad.IL-5) gene or a control adenovirus (Ad.delete) ± oxazolone. The effect of H. diminuta+oxazolone in CCL11/CCL22 (eotaxin-1 and 2) knockout (KO) mice was determined. Helminth infection and Ad.IL-5 treatment increased IL-5 and eosinophil numbers. In vivo neutralization of IL-5 significantly reduced the severity of colitis in H. diminuta+oxazolone-treated mice, and H. diminuta did not exaggerate oxazolone-induced colitis in CCL11/CCL22 KO mice. Mice receiving Ad.IL-5 only had no colitis, while oxazolone-induced colitis was more severe in animals cotreated with Ad.IL-5 (Ad.delete + oxazolone was not significantly different from oxazolone only). Thus, while there is much to be gleaned about antiinflammatory mechanisms from rodent-helminth model systems, these data illustrate the caveat that infection with helminth parasites as a therapy could be contraindicated in patients with eosinophilia or elevated IL-5 unless coupled to appropriate measures to block IL-5 and/or eosinophil activity. The potential of infection with parasitic helminths to reduce the severity of concomitant disease has been the focus of a cadre of investigators, who, using a variety of model systems, have produced substantial proof-of-concept data that infection with nematode, trematode, or cestode parasites reduces disease in animal models of inflammatory and autoimmune disease.1McKay DM The therapeutic helminth?.Trends Parasitol. 2009; 25: 109-114Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar Collectively, these studies have shown that as a consequence of the host response to infection with helminth parasites, there is mobilization of transforming growth factor (TGF)-β, interleukin (IL)-10, Foxp3+ regulatory T cells, alternatively activated macrophages, and inhibition of IL-17– and interferon (IFN)-γ–driven events: one, or a combination, of these events could block the development of autoimmune and inflammatory disorders.2Ince MN Elliott DE Setiawan T Metwali A Blum A Chen HL Urban JF Flavell RA Weinstock JV Role of T cell TGF-β signaling in intestinal cytokine responses and helminthic immune modulation.Eur J Immunol. 2009; 39: 1870-1878Crossref PubMed Scopus (71) Google Scholar, 3Hunter MM Wang A Hirota CL McKay DM Neutralizing anti-IL-10 antibody blocks the protective effect of tapeworm infection in a murine model of chemically-induced colitis.J Immunol. 2005; 174: 7368-7375Crossref PubMed Scopus (144) Google Scholar, 4Elliott DE Metwali A Leung J Setiawan T Blum AM Ince MN Bazzone LE Stadecker MJ Urban Jr, JF Weinstock JV Colonization with Heligmosomoides polygyrus suppresses mucosal IL-17 production.J Immunol. 2008; 181: 2414-2419Crossref PubMed Scopus (89) Google Scholar, 5Khan WI Blennerhassett PA Varghese AK Chowdhury SK Omsted P Deng Y Collins SM Intestinal nematode infection ameliorates experimental colitis in mice.Infect Immunity. 2002; 71: 5931-5937Crossref Scopus (221) Google Scholar, 6Wilson MS Taylor MD Balic A Finney CA Lamb JR Maizels RM Suppression of allergic airway inflammation by helminth-induced regulatory T cells.J Exp Med. 2005; 202: 1199-1212Crossref PubMed Scopus (501) Google Scholar, 7Smith P Mangan NE Walsh CM Fallon RE McKenzie AN van Nooijen RN Fallon PG Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism.J Immunol. 2007; 178: 4557-4566Crossref PubMed Scopus (234) Google Scholar These findings have been complemented by intriguing data suggesting that infection with viable parasitic nematodes could be a treatment for patients with inflammatory bowel disease (IBD)8Summers RW Elliott DE Urban Jr, JF Thompson RA Weinstock JV Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial.Gastroenterology. 2005; 128: 825-832Abstract Full Text Full Text PDF PubMed Scopus (601) Google Scholar or asthma,9Mortimer K Brown A Feary J Jagger C Lewis S Antoniak M Pritchard D Britton J Dose-ranging study for trials of therapeutic infection with Necator americanus in humans.Am J Trop Med Hyg. 2006; 75: 914-920PubMed Google Scholar whose condition is not managed by conventional therapies. We have contributed to the concept of ‘helminth therapy,’ noting that while specific helminths may be identified that can be used as a treatment, the information gleaned from analyses of helminth-rodent model systems could also be the basis for the development of novel therapeutic approaches.10Hunter MM Wang A Parhar KS Johnston MJ van Nooijen R Beck PL McKay DM In vitro-derived alternatively activated macrophages reduce colonic inflammation in mice.Gastroenterology. 2010; 138: 1395-1405Abstract Full Text Full Text PDF PubMed Scopus (228) Google Scholar However, parasitism comes at a cost to the host, and many species take a huge toll on human health and well-being.11Hotez PJ Brindley PJ Bethony JM King CH Pearce EJ Jacobson J Helminth infections: the great neglected tropical diseases.J Clin Invest. 2008; 118: 1311-1321Crossref PubMed Scopus (1045) Google Scholar This coupled to the spectre of iatrogenic disease12van Kruiningen HJ West AB Iatrogenic Trichuris suis infection.Arch Pathol Lab Med. 2007; 131: 180-181PubMed Google Scholar means that one must be vigilant of the potential for infection with helminth parasites to exaggerate disease, and to provoke deleterious side-effects. In this context, we showed that in contrast to the dinitrobenzene sulfonic acid (DNBS) model of colitis,3Hunter MM Wang A Hirota CL McKay DM Neutralizing anti-IL-10 antibody blocks the protective effect of tapeworm infection in a murine model of chemically-induced colitis.J Immunol. 2005; 174: 7368-7375Crossref PubMed Scopus (144) Google Scholar mice infected with the rat tapeworm Hymenolepis diminuta developed significantly more severe colonic inflammation when challenged intrarectally (ir.) with oxazolone.13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Grossly, DNBS and oxazolone-induced colitis in mice look similar but they are different in etiology and histopathology: one of the more notable differences being an increase in eosinophils in the colon of oxazolone-treated mice.14Boirivant M Fuss I Chu A Strober W Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4.J Exp Med. 1998; 188: 1929-1939Crossref PubMed Scopus (437) Google Scholar, 15Heller F Fuss IJ Nieuwenhuis EE Blumberg RS Strober W Oxazolone colitis, a Th2 colitis model resembling ulcerative colitis, is mediated by IL-13 producing NK-T cells.Immunity. 2002; 17: 629-638Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar Because a stereotypic human and murine response to infection with helminth parasites is eosinophilia, we hypothesized that the enhancement of oxazolone-induced colitis by infection with H. diminuta could be due to IL-5 and consequently eosinophils. To test this postulate, i) H. diminuta+oxazolone–treated mice were administered anti–IL-5 antibodies, and ii) mice were treated with adenovirus carrying the murine IL-5 gene ± oxazolone. In vivo neutralization of IL-5 blocked the enhanced colitis that develops in H. diminuta+oxazolone treated mice and in accordance with these data, overexpression of IL-5 resulted in a more severe disease in oxazolone cotreated mice. Many variables are at play in animal models, and while none fully recapitulate human disease, we present these data as a caveat that individuals with eosinophilia may not be good candidates for ‘helminth therapy,’ unless this is coupled with other therapeutics to block the effects of IL-5 and/or other eosinophil-derived molecules. Colitis was induced in anesthetized male BALB/c mice (7–9 weeks old; Charles River Animal suppliers, Quebec, Canada), BALB/c mice engineered to lack CCL11/CCL22 (kindly provided by Dr. M. Rothenberg, University of Cincinnati, Ohio16Rothenberg ME MacLean JA Pearlman E Luster AD Leder P Targeted disruption of the chemokine eotaxin partially reduces antigen-induced tissue eosinophilia.J Exp Med. 1997; 185: 785-790Crossref PubMed Scopus (473) Google Scholar) and BALB/c mice lacking the α chain of the IL-4 receptor (IL-4Rα: kindly provided by Dr. F. Brombacher, University of Cape Town, South Africa) via the intrarectal (ir.) delivery of 3 or 4 mg of oxazolone in 100 μl of 1:1 PBS:ethanol using a 3-cm lubricated polyethylene catheter.13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Time-matched vehicle-only treated mice served as controls. Mice were humanely sacrificed 72 hours postoxazolone treatment. Some studies using oxazolone use a sensitization and ir. rechallenge protocol.14Boirivant M Fuss I Chu A Strober W Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4.J Exp Med. 1998; 188: 1929-1939Crossref PubMed Scopus (437) Google Scholar We opted to use a single ir. delivery in accordance with our earlier study and for comparisons with the DNBS model of colitis.3Hunter MM Wang A Hirota CL McKay DM Neutralizing anti-IL-10 antibody blocks the protective effect of tapeworm infection in a murine model of chemically-induced colitis.J Immunol. 2005; 174: 7368-7375Crossref PubMed Scopus (144) Google Scholar Experiments conformed to the Canadian guidelines for animal welfare. The adenovirus used was engineered to lack the E1 region and thus was replication-deficient and had the murine IL-5 gene inserted into its genome (Ad.IL-5).17Bramson JL Graham FL Gauldie J The use of adenoviral vectors for gene therapy and gene transfer in vivo.Curr Opin Biotech. 1995; 6: 590-595Crossref PubMed Scopus (99) Google Scholar Replication-deficient adenovirus with no additional gene insertions (ie, Ad.delete) were used as a control.17Bramson JL Graham FL Gauldie J The use of adenoviral vectors for gene therapy and gene transfer in vivo.Curr Opin Biotech. 1995; 6: 590-595Crossref PubMed Scopus (99) Google Scholar Under light anesthesia, mice received an intraperitoneal injection of either Ad.IL-5 or Ad.delete [108 plaque forming units (pfu) of adenovirus/100 μl sterile PBS: adenovirus kindly provided by Dr. Z. Xing, McMaster University, Hamilton, ON, Canada] and 48 hours later were randomized into those receiving PBS or oxazolone. Mice under manual restraint received an oral gavage of 100 μl of sterile PBS containing five viable cysticercoids of H. diminuta and were challenged with oxazolone 8 days later.13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Other mice were administered a total of 200 μg of anti–IL-5 (TRK5, a rat IgG1: Cat# MM550C Pierce Endogen, Rockford, IL) delivered i.p. to lightly anesthetized mice 5 (50 μg AB), 7 (100 μg AB) and 9 (50 μg AB) days postinfection (with oxazolone treatment at 8 days postinfection).3Hunter MM Wang A Hirota CL McKay DM Neutralizing anti-IL-10 antibody blocks the protective effect of tapeworm infection in a murine model of chemically-induced colitis.J Immunol. 2005; 174: 7368-7375Crossref PubMed Scopus (144) Google Scholar Time-matched controls consisted of oxazolone+ anti–IL-5 treatment and mice treated with an irrelevant rat IgG1 (Biolegend, San Diego, CA). After oxazolone treatment the mice were monitored daily for signs of disease, including diarrhea (ie, wet or faecal-stained anus), weight loss, and behavioral changes (eg, lethargy, ruffled fur). At sacrifice, the entire colon was excised, weighed, and examined for signs of damage/ulceration. A disease activity score (DAS) was determined using a 5 point-scale: >10% drop in body weight (0 or 1); soft/loose stool, empty colon, wet anus (0 or 1); evidence of active bleeding or occult blood (0 or 1); presence of macroscopic ulcers (0 or 1); a maximum score of 5 was given if any animal had to be humanely sacrificed because of reaching a pre-determined end-point in disease severity.13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Because colitis results in shortening of the colon, colons were divided based on percentage of total length: the distal 10% was discarded, the next 20% was frozen in liquid nitrogen for use in the myeloperoxidase (MPO; an indicator of granulocyte infiltrate) and eosinophil peroxidase (EPO) assay, and the next 20% (ie, the most proximal segment) was fixed in formalin for histological analysis. MPO (a marker of acute inflammation often associated with neutrophil infiltration) and EPO (a specific eosinophil marker) activities were determined in tissue extracts and the human acute promyelocytic leukemia cell line, HL-60 (clone 15) (ATCC), differentiated into eosinophils by culture for 7 days with 0.5 mmol/L butyric acid (Sigma Chemical Co.) and 5 ng/ml granulocyte macrophage colony stimulating factor (GM-CSF: R & D systems)18Michail S Abernathy F A new model for studying eosinophil migration across cultured intestinal epithelial monolayers.J Pediatr Gastroenterol Nutr. 2004; 39: 56-63Crossref PubMed Scopus (11) Google Scholar via a colorimetric kinetic assay in which H2O2 catabolism is measured. One unit of MPO activity in the samples is the amount of enzyme required to degrade 1 μmol/L H2O2/minute. The assay was repeated in the presence of 50 mmol/L 3-amino-1,2,4-triazole (AMT: Sigma Chemical Co.) to inhibit EPO, whose activity was calculated by subtracting the MPO+AMT value from the MPO value only.13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Segments of the colon were immersion-fixed in 10% buffered formalin (72 hours), dehydrated in graded alcohols, cleared in xylene, and embedded in paraffin wax. Sections (3 μm) were collected on coded slides, stained with hematoxylin and eosin and a histological damage score calculated on 12-point scale as previously described.13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Eosinophils were counted in 5 random high power (×40 objective) fields (HPF) of view. Serum was obtained from murine blood samples 24 hours after Ad.IL-5 injection and in additional studies 72 hours after oxazolone and stored at −80°C. Interleukin-5 levels were determined by ELISA. Spleen cells, mesenteric lymph node (MLN) cells, or colonic lamina propria lymphocytes (LPLs)19Reardon C Wang A McKay DM Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death.J Immunol. 2008; 180: 8316-8326Crossref PubMed Scopus (36) Google Scholar were isolated and 5 × 106 cells stimulated with concanavalin A (ConA: 2 μg/ml) for 48 hours, cell-free supernatants collected, and levels of IL-4, IL-5, and IL-10 measured. All ELISAs were performed in duplicate using antibody pairs from R&D Systems (Minneapolis, MN) and each assay had a limit of detection of 8 pg/ml. Blood smears or cytospin preparations of bone-marrow cells retrieved from murine femurs were stained using the Hema3 differential staining kit (Fisher Scientific, Kalamazoo, MI) and mononuclear cells, neutrophils, and eosinophils counted. One million cells of the human colon-derived T84 cell line were seeded onto porous filter supports and cultured as described20McKay DM Croitoru K Perdue MH T cell monocyte interactions regulate epithelial physiology in a co-culture model of inflammation.Am J Physiol Cell Physiol. 1996; 270: C418-C428PubMed Google Scholar (human cell lines were used for these studies because of the lack of a mouse colon-derived epithelial cell line suitable for use in barrier studies). On reaching confluence (defined as transepithelial resistance (TER) ≥750 Ω/cm2), monolayers were cultured with 1 × 105 HL-60 eosinophils (in the basal compartment of the culture well) ± LPS (Escherichia coli, 100 ng/ml; Sigma Chemical Co.) and epithelial barrier function assessed by measurements of TER and the lumen to basal flux of horseradish peroxidase (HRP) after a 48-hour period: i) TER was measured using a voltmeter and matched electrodes (Millipore) at the beginning and end of the experiments and is presented as percentage of pretreatment values21Lampinen M Carlson M Sangfelt P Taha Y Thorn M Loof L Raab Y Venge P IL-5 and TNF-α participate in recruitment of eosinophils to intestinal mucosa in ulcerative colitis.Dig Dis Sci. 2001; 46: 2004-2009Crossref PubMed Scopus (66) Google Scholar; ii) HRP (20 ng type VI; Sigma Chemical Co.) was added to the apical chamber (1 ml vol.) of the well and three 10 μl samples of culture medium were collected from the basolateral chamber, diluted (1:10) in 0.5% HTAB buffer and enzymatic activity determined by spectrophotometric measurement (OD450nm) of 3,3′,5,5′-tetramethylbenzidine (TMB) oxidation after the reaction was terminated with 2N H2SO4, and HRP determined against a concentration curve. All data are presented as the mean ± SEM, where n is the total number of mice. Statistical comparisons were performed via one-way analysis of variance, followed by post hoc pair-wise comparisons of the groups with either Student's t-test or Tukey's test, as appropriate and P < 0.05 set as a statistically significant difference. Direct ir. instillation of oxazolone resulted in an acute and self-resolving colitis: disease severity peaking 1–3 days posttreatment, with significant spontaneous healing by day 7 posttreatment (n = 6–7 mice; data not shown).13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar Normal BALB/c animals completely expel H. diminuta, whereas intestinal washings from IL-4Rα KO mice revealed that these animals failed to spontaneously reject the helminth. Eleven days after infection 12 H. diminuta (length range = 8–12 cm; total biomass = 269.5 mg) were retrieved from the small intestine of 3 IL-4Rα KO mice (nb. each mouse given 5 cysticercoids), whereas no worms were obtained from time-matched identically infected wild-type BALB/c mice. Oxazolone-induced colitis in IL-4Rα KO mice was less severe than that observed in wild-type BALB/c mice (DAS = 3.8 ± 0.5 and 1.8 ± 0.5* for wild-type and IL-4Rα KO mice respectively (n = 7 mice, *P < 0.05), affirming a role for IL-4Rα signaling in the disease process and this is consistent with other studies using this model system.14Boirivant M Fuss I Chu A Strober W Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4.J Exp Med. 1998; 188: 1929-1939Crossref PubMed Scopus (437) Google Scholar Successful infection with H. diminuta in BALB/c mice was confirmed by elevated IL-4 production from ConA-stimulated spleen cells: H. diminuta+oxazolone = 368 ± 144*, H. diminuta+oxazolone+anti–IL-5 = 898 ± 302*, control = 106 ± 19 pg/ml (n = 4; *, P < 0.05 compared to control). Furthermore, IL-5 production by conA-stimulated spleen cells and LPLs was significantly increased in cells from H. diminuta-infected mice ± oxazolone treatment (Figure 1, A and B), and this was paralleled by increased eosinophil production by the bone-marrow (Figure 1C), and eosinophil numbers in the blood (Figure 1D) and colon (Figure 1, E and F). Analysis of circulating and colonic eosinophils revealed no significant differences between naïve mice and those treated with oxazolone+H. diminuta+anti–IL-5 AB (Figure 1, D and E). Consistent with earlier findings, oxazolone-induced colitis was characterized by loss of body weight (Figure 2A), shortening of the colon (Figure 2B), increased disease activity scores (Figure 2C), and significant histopathology (Figure 3, A and B). Administration of anti–IL-5 AB did not affect the outcome of oxazolone-induced colitis (n = 4; Figure 2), suggesting that while eosinophils are recruited to the colon14Boirivant M Fuss I Chu A Strober W Oxazolone colitis: a murine model of T helper cell type 2 colitis treatable with antibodies to interleukin 4.J Exp Med. 1998; 188: 1929-1939Crossref PubMed Scopus (437) Google Scholar their overall contribution to oxazolone-induced colitis is small and masked within the natural variation between mice in their response to oxazolone. Oxazolone-induced colitis was more severe in mice previously infected with H. diminuta (Figures 2 and 3)13Hunter MM Wang A McKay DM Helminth infection enhances disease in a murine TH2 model of colitis.Gastroenterology. 2007; 132: 1320-1330Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar; however, animals that also received anti–IL-5 AB had less colitis than H. diminuta+oxazolone treated mice and were similar in phenotype to naïve mice. Mice infected with H. diminuta and treated with oxazolone and irrelevant IgG1 had severe colitis (Figures 2 and 3) that was not statistically different from that in H. diminuta+oxazolone–treated mice. These data support an IL-5-eosinophil axis in the exaggeration of oxazolone-induced colitis in H. diminuta–infected mice.Figure 3A: histology damage scores in oxazolone (OX) ± H. diminuta ± anti–IL-5 antibody-treated mice [mean ± SEM; n = 7–8 mice from two experiments; assessment conducted 72 hours after oxazolone (OX); *P < 0.05 compared to control, **P < 0.05 compared to oxazolone, and †P < 0.05 compared to and H. d+oxazolone+anti–IL-5 AB, respectively; iAB, irrelevant antibody (IgG1)]. B: depicts the number of mice/group with the most severe histological damage as assessed by histological damage scores greater than or equal to 9.View Large Image Figure ViewerDownload Hi-res image Download (PPT) CCL11/CCL22 KO mice developed colitis in response to topical application of oxazolone that was similar to that observed in wild-type BALB/c mice (Figure 4, A–C). This is consistent with in vivo neutralization of IL-5 having no effect on the outcome of ozaxolone-induced colitis in normal mice (Figure 2, A–C). In contrast to normal BALB/c mice, infection with H. diminuta did not exaggerate oxazolone-induced colitis in CCL11/CCL22 KO as gauged by all parameters of disease: disease activity scores, representative histological images and histological damage scores are shown in Figure 4. Indeed, prior infection with H. diminuta led to a degree of protection against oxazolone-induced colitis (Figure 4). Enumeration of eosinophils in histological sections of colons from control (n = 7), oxazolone (n = 6), and H. diminuta+ ozaxolone (n = 6)–treated CCL11/CCL22 KO revealed ≤5 eosinophils/HPF, with the majority of HPF containing only 0–2 eosinophils. Thus, while eosinophil influx may characterize oxazolone-induced colitis, they are not a prerequisite for disease and significant colitis can develop in the absence of eosinophils as shown by this assessment of CCL11/CCL22 KO mice. Serum levels of IL-5 24 hours after injection of Ad.IL-5 were 488 ± 55* pg/ml compared to controls at 139 ± 21 pg/ml (n = 4; *, P < 0.05), confirming bioactivity of the adenovirus. Similarly, levels of IL-5 were significantly increased in sera from Ad.IL-5 or oxazolone+Ad.IL-5–treated mice at the end of the experiment (Figure 5). Analysis revealed no statistical differences in the colon of ethanol-treated control mice and mice receiving either Ad.IL-5 or Ad.delete only and this dose of nonreplicating adenovirus did not evoke an increase in blood polymorphonuclear (PMNs) immune cells: control = 29 ± 5% versus Ad.IL5 = 27 ± 5% of blood immune cells. In contrast, mice treated with Ad.IL-5+oxazolone or Ad.delete+oxazolone displayed significant increases in PMNs (n = 4), of 61 ± 11% and 58 ± 9% of blood leukocyte, respectively. In addition, mice treated with Ad.IL-5 ± oxazolone had increased numbers of eosinophils in the colon: control = 9 ± 3, Ad.IL-5 = 28 ± 3*, oxazolone = 19 ± 4,* Ad.IL-5+oxazolone = 23 ± 2* and Ad.delete+oxazolone = 18 ± 4* eosinophils/HPF of view (n = 3–4; *, P < 0.05 compared to control). There was no difference between the oxazolone- and Ad.IL-5+oxazolone–treated mice in terms of absolute eosinophil numbers, but this gives no indication of the activation status of the recruited cells. These histological observations were supported by significant increases in EPO levels in colonic segments excised from oxazolone±adenovirus treated mice as compared to naïve mice or mice injected with Ad.IL-5 or Ad.delete only (data not shown). Mice cotreated with oxazolone+Ad.delete had, on average, slightly more severe disease (likely reflecting a response to the small dose of virus); however, there were no statistical differences in the colitis in Ad.delete+ oxazolone compared to oxazolone-treated mice. In contrast, mice that received Ad.IL-5+oxazolone displayed a significant increase in the severity of the colitis (Figure 6, A–C): histological examination revealed greater derangement of colonic architecture, more inflammatory cell infiltrate, and more extensive epithelial erosion and ulceration (Figure 7). Colonic levels of MPO activity were quite variable between experiments, and were statistically significantly increased in tissues from oxazolone (0.9 ± 0.2,* n = 18), oxazolone+Ad.IL-5 (1.8 ± 0.4,*#n = 18) and oxazolone+Ad.delete (0.7 ± 0.2,* n = 9) treated mice compared to those from control mice (0.3 ± 0.05 U/mg tissue, n = 18) (*, P < 0.05 compared to control; #, P < 0.05 compared to oxazolone and oxazolone+Ad.delete).Figure 7Representative images of H&E sections of the colon from the various groups of mice with the resultant histological damage scores from control (con), oxazolone (3 mg ir, +72 hours) and oxazolone+Ad.delete or Ad.IL-5 (108 pfu, ip.)-treated mice (mean ± SEM; n = 9–18 from 3 to 5 experiments; *P < 0.05 compared to control and **P < 0.05 compared to oxazolone, respectively; m, muscle; l, lumen; arrowhead, friable epithelium; arrow, inflammatory infiltrate; asterisk, ulceration; original magnification, ×200).View Large Image Figure ViewerDownload Hi-res image Download (PPT) A 48-hour exposure to eosinophils or LPS only had negligible effects on the barrier function of T84 epithelial cell monolayers. However, coculture with the HL-60 eosinophil cell line exposed to 100 ng/ml of E. coli LPS had a significant impact on epithelial permeability as shown by a drop in transepithelial resistance of ∼40% and a fourfold increase in the transepithelial flux of HRP (Figure 8, A and B). Consistent with our earlier studies,21Lampinen M Carlson M Sangfelt P Taha Y Thorn M Loof L Raab Y Venge P IL-5 and TNF-α participate in recruitment of eosinophils to intestinal mucosa in ulcerative colitis.Dig Dis Sci. 2001; 46: 2004-2009Crossref PubMed Scopus (66) Google Scholar ConA stimulation of spleen cell or lamina propria lymphocyte cultures from mice infected 11 days previously with H. diminuta ± oxazolone" @default.
• W2129589060 created "2016-06-24" @default.
• W2129589060 creator A5050995193 @default.
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• W2129589060 date "2010-12-01" @default.
• W2129589060 modified "2023-10-16" @default.
• W2129589060 title "Exacerbation of Oxazolone Colitis by Infection with the Helminth Hymenolepis diminuta" @default.
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