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Infection with H. diminuta increases the capacity of splenocytes from young and adult mice to produce Th2- type cytokines
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Infection with helminth parasites reduces the severity of concomitant inflammatory disease in adult mice. There is an alarming increase of IBD in children. It is important to determine if helminth therapy would be of value in pediatric IBD, and if triggering immunological memory to the worm would be anti-colitic. Three-week (young) and eight-week (...
Context in source publication
Context 1
... expulsion of H. diminuta, the young mice (male and female data combined) mobilized antihelminth effector events that included blood eosinophilia ( Fig. 2A), intestinal goblet cell hyperplasia (Fig. 2B), and increased intestinal levels of IgG 1 (Fig. 2C). Similarly, Th2 polarization as assessed by concanavalin-A stimulation of splenocytes was observed with cells from young and adult mice (Table 1). Time-course analyses revealed that the kinetics of the effector cell responses to infection with H. diminuta were very similar between young and adult mice, with the peak response slightly delayed or reduced in magnitude in the young mice. ...Similar publications
Two experimental paradigms were adopted to explore host–helminth interactions involved in the regulation of colitis and to understand if colitis affects the outcome of helminth infection. First, male BALB/c mice infected with H. diminuta were challenged 4 days later with dinitrobenzene sulphonic acid (DNBS) and necropsied 3 days later. Second, mice...
Citations
... Fan et al. (2004) found that immunization with non-viable oncospheres of H. diminuta offered complete protection against infection by homologous parasites in rats or mice [71]. In turn, Arai et al. (2018) report that a crude worm extract of H. diminuta inducing an immune response in previously infected mice could be used to limit the severity of colitis, regardless of the age of the host [72]. Smyth et al. (2017) assessed the suitability of H. diminuta cysticercoids (HDC) as anti-inflammatory therapeutics. ...
... Fan et al. (2004) found that immunization with non-viable oncospheres of H. diminuta offered complete protection against infection by homologous parasites in rats or mice [71]. In turn, Arai et al. (2018) report that a crude worm extract of H. diminuta inducing an immune response in previously infected mice could be used to limit the severity of colitis, regardless of the age of the host [72]. Smyth et al. (2017) assessed the suitability of H. diminuta cysticercoids (HDC) as anti-inflammatory therapeutics. ...
The tapeworm Hymenolepis diminuta is a common parasite of the small intestine in rodents but it can also infect humans. Due to its characteristics and ease of maintenance in the laboratory, H. diminuta is also an important model species in studies of cestodiasis, including the search for new drugs, treatments, diagnostics and biochemical processes, as well as its host–parasite interrelationships. A great deal of attention has been devoted to the immune response caused by H. diminuta in the host, and several studies indicate that infection with H. diminuta can reduce the severity of concomitant disease. Here, we present a critical review of the experimental research conducted with the use of H. diminuta as a model organism for over more than two decades (in the 21st century). The present review evaluates the tapeworm H. diminuta as a model organism for studying the molecular biology, biochemistry and immunology aspects of parasitology, as well as certain clinical applications. It also systematizes the latest research on this species. Its findings may contribute to a better understanding of the biology of tapeworms and their adaptation to parasitism, including complex correlations between H. diminuta and invertebrate and vertebrate hosts. It places particular emphasis on its value for the further development of modern experimental parasitology.
... Studies with H. diminuta in the dextran sodium sulphate (DSS) [9] and di-nitrobenzene sulphonic acid (DNBS) [3] murine models of colitis were among the first to provide proof-of-concept data in support of helminth therapy to reduce the severity of colonic inflammation and concomitant signs of disease. While ongoing studies have confirmed the anti-colitic effect in the DNBS-model and revealed some of the nuances of the helminth-host interaction [10][11][12], two major questions remain unaddressed: both germane to helminth therapy: First, what is the temporal window of opportunity for H. diminuta to suppress colitis? Elucidation of the kinetics of infection in the context of inflammation can provide insight into host-parasite interaction and potentially reveal new targets for therapeutic intervention. ...
... Three-week-old mice infected with H. diminuta were also protected from DNBSinduced colitis; however, the kinetics of this response differed from adult mice: young mice displayed less colitis when infected 10 days, but not 8 days, prior to treatment with DNBS [10]. This delay in the anti-colitic effect could be due to immaturity of the immune system in the young mouse, and it draws attention to the importance of the kinetics of the infection-colitis regimen. ...
Two experimental paradigms were adopted to explore host–helminth interactions involved in the regulation of colitis and to understand if colitis affects the outcome of helminth infection. First, male BALB/c mice infected with H. diminuta were challenged 4 days later with dinitrobenzene sulphonic acid (DNBS) and necropsied 3 days later. Second, mice were infected with H. diminuta 3 days after DNBS treatment and necropsied 11 or 14 days post-DNBS. Mice were assessed for colitic disease severity and infectivity with H. diminuta upon necropsy. Supporting the concept of helminth therapy, mice are protected from DNBS–colitis when infected with H. diminuta only 4 days previously, along with parallel increases in splenic production of Th2 cytokines. In the treatment regimen, H. diminuta infection produced a subtle, statistically significant, enhanced recovery from DNBS. Mice regained body weight quicker, had normalized colon lengths, and showed no overt signs of disease, in comparison to the DNBS-only mice, some of which displayed signs of mild disease at 14 days post-DNBS. Unexpectedly, colitis did not affect the hosts’ anti-worm response. The impact of inflammatory disease on helminth infection is deserving of study in a variety of models as auto-inflammatory diseases emerge in world regions where parasitic helminths are endemic.
... The level of IFN-g in the colon was significantly elevated in the mice from TNBS group (1178.0 ± (25)(26)(27). Previously, we have demonstrated that infection of Trichinella spiralis reduce the severity of TNBS -induced colitis (28). However, helminth therapy is hard to accept for patients because of many ethical issues that might be raised. ...
Trichinella spiralis induced alternative activated macrophages (M2), leading to protect against Crohn’s disease, known as Th1 –related inflammation, which enhances oxidative stress in the host. However, the relationship of oxidative stress and T. spiralis –mediated immune response is still unknown. In our study, we showed that nuclear factor erythroid 2-related factor-2 (Nrf2), a key transcription factor in antioxidant, participated in M2 polarization induced by T. spiralis muscle larval excretory/secretory (ES) products in vitro. ES –treated M2 were injected intravenously after TNBS challenge and we demonstrated that ES-M could alleviate the severity of the colitis in mice. Adoptive transfer of ES –treated M2 decreased the level of IFN-γ and increased the levels of IL-4 and IL-10 in vivo. However, the capacity of ES –treated Nrf2 KO macrophages to treat colitis was dramatically impaired. ES –treated Nrf2 KO macrophages was insufficient to result in the elevated levels of IL-4 and IL-10. These findings indicate that Nrf2 was required for M2 polarization induced by T. spiralis ES to alleviate colitis in mice.
... 67 In another study, mice infected with Hymenolepis diminuta were protected from chemical colitis, while in those previously infected mice, H. diminuta antigen triggered an immunological memory response with increased IL-4 and -10 that reduced the severity of chemical colitis. 68 Schistosomes also modulate experimental colitis. In a study of rat immunisation with a recombinant schistosome enzymatic protein, chemical colitis was attenuated through eosinophil-dependent modulation of the immune system towards a Th2 profile, with local and systemic increases in IL-13 and IL-5. ...
Background
The initiating events of chronic gastrointestinal (GI) inflammation in Crohn's disease (CD) and ulcerative colitis (UC) are not well‐defined, but GI infections are implicated.
Aims
To define the role of GI infections in risk of incident inflammatory bowel disease (IBD) and synthesise the current body of relevant translational data to provide biological context for associations between GI infections and IBD risk.
Methods
We systematically reviewed electronic databases through February 2020. Clinical studies that provided risk estimates of the association between GI infections and incident IBD were included. Inclusion criteria were broader for translational studies aiming to define mechanisms of GI infections and predisposition to or protection from IBD.
Results
Of the studies identified, 63 met full inclusion criteria. Among studies of clinical gastroenteritis, bacteria—specifically, Salmonella species, Campylobacter species and Clostridioides difficile—demonstrated consistent positive associations with risk of incident IBD. Of viruses, norovirus was associated with increased risk of incident CD. Regarding inverse associations with incident IBD, Helicobacter pylori and helminth infections were associated with a generally consistent reduced risk of IBD. Based on a qualitative analysis of the translational data, putative mechanisms involve multiple microbial and immunologic pathways.
Conclusions
Based on this systematic review, certain enteric pathogens are associated with an increased risk of incident IBD, while others are potentially protective. Prospective studies are required to clarify the clinical implications of these enteric pathogens on the risk and course of IBD, not to mention possible therapeutic or preventative benefit.
... Colitis was induced in 7-to 9-week-old male BALB/c mice (Charles River Labs, Sherbrooke, QC, Canada) with DSS (5%, 40 kDa; Affymetrix, Santa Clara, CA) drinking water for 5 days, then 3 days normal water) or DNBS (3 mg, intrarectal Q10 , 72 hours). 6,49 Animals were weighed and observed daily and humanely killed if they lost >20% weight. At necropsy, the colon was excised and measured, and a macroscopic disease score was calculated. ...
... 6,49 A portion of mid-colon was fixed and paraffin-embedded; sections were collected on coded slides and H&E stained; and histopathology was scored in a blinded fashion on a 0-12 scale. 6,49 Other sections were immunostained for the proliferationrelated antigen Ki67 (1:400 dilution, Abcam ab15580; Abcam, Cambridge, UK), and apoptotic/death/DNA damaged cells were identified in the section by using TUNEL staining and following the manufacturer's recommendations (In Situ Cell Death Detection kit, TMR Red; Roche, Basel, Switzerland). P110 (a gift from Dr D. Mochly-Rosen, Stanford University) was administered daily (3 mg/kg, intraperitoneal), 24 as depicted in the figures. ...
... -48 DSS may activate macrophages,49 ...
Objective
Mitochondria exist in a constantly remodelling network, and excessive fragmentation can be pathophysiological. Mitochondrial dysfunction can accompany enteric inflammation, but any contribution of altered mitochondrial dynamics (i.e. fission/fusion) to gut inflammation is unknown. We hypothesised that perturbed mitochondrial dynamics would contribute to colitis.
Design
qPCR for markers of mitochondrial fission and fusion was applied to tissue from dextran sodium-sulphate (DSS)-treated mice. An inhibitor of mitochondrial fission, P110 (prevents dynamin related protein (Drp)-1 binding to mitochondrial fission 1 protein (Fis1)), was tested in the DSS and di-nitrobenzene sulphonic acid (DNBS) models of murine colitis and the impact of DSS ± P110 on intestinal epithelial and macrophage mitochondria assessed in vitro.
Results
Analysis of colonic tissue from mice with DSS-colitis revealed increased mRNA for molecules associated with mitochondrial fission (i.e. Drp1, Fis1) and fusion (optic atrophy factor 1), and increased phospho-Drp1 compared to control. Systemic delivery of P110, in prophylactic or treatment regimens, reduced the severity of DSS- or DNBS-colitis, and the subsequent hyperalgesia in DNBS-mice. Application of DSS to epithelial cells or macrophages caused mitochondrial fragmentation. DSS-evoked perturbation of epithelial cell energetics and mitochondrial fragmentation, but not cell death, were ameliorated by in vitro co-treatment with P110.
Conclusion
We speculate that the anti-colitic effect of systemic delivery of the anti-fission drug, P110, works, at least partially, by maintaining enterocyte and macrophage mitochondrial networks. Perturbed mitochondrial dynamics can be a feature of intestinal inflammation, the suppression of which is a potential novel therapeutic direction in inflammatory bowel disease.
... Numerous reports describe the mechanisms of influence of H. diminuta on the production of interleukins in colitis. Melon (2010), Arai (2018) and Johnston (2010) have shown the inhibition of dinitrobenzenesulfonic acid-induced colitis (DNBS) by increased production of IL-4 and IL-10 in mice infected with rat tapeworm [12,112,113]. In addition, Johnston (2010) observed decreased TNF-α secretion in mice infected with H. diminuta [12]. ...
... showed that CD19+ lymphocytes from H. diminuta-infected mice reduced the effects of DNBS, and thus promoted the suppression of colitis [115]. In turn, Arai et al. (2018) showed that the H. diminuta antigen inducing an immune response in previously infected mice could be used to limit the severity of colitis regardless of the age of the host [118]. Graepel (2013) [111] found an exacerbation of the disease as a result of H. diminuta infection in a mouse with rheumatoid arthritis. ...
... showed that CD19+ lymphocytes from H. diminuta-infected mice reduced the effects of DNBS, and thus promoted the suppression of colitis [115]. In turn, Arai et al. (2018) showed that the H. diminuta antigen inducing an immune response in previously infected mice could be used to limit the severity of colitis regardless of the age of the host [118]. Graepel (2013) [111] found an exacerbation of the disease as a result of H. diminuta infection in a mouse with rheumatoid arthritis. ...
The rat tapeworm Hymenolepis diminuta is a parasite of the small intestine of rodents (mainly mice and rats), and accidentally humans. It is classified as a non-invasive tapeworm due to the lack of hooks on the tapeworm’s scolex, which could cause mechanical damage to host tissues. However, many studies have shown that metabolites secreted by H. diminuta interfere with the functioning of the host’s gastrointestinal tract, causing an increase in salivary secretion, suppression of gastric acid secretion, and an increase in the trypsin activity in the duodenum chyme. Our work presents the biochemical and molecular mechanisms of a parasite-host interaction, including the influence on ion transport and host intestinal microflora, morphology and biochemical parameters of blood, secretion of antioxidant enzymes, expression of Toll-like receptors, mechanisms of immune response, as well as the expression and activity of cyclooxygenases. We emphasize the interrelations between the parasite and the host at the cellular level resulting from the direct impact of the parasite as well as host defense reactions that lead to changes in the host’s tissues and organs.
Inflammatory bowel disease (IBD) is associated with a dysregulated mucosal immune response in the gastrointestinal tract. The number of patients with IBD has increased worldwide, especially in highly industrialized western societies. The population of patients with IBD in North America is forecasted to reach about four million by 2030; meanwhile, there is no definitive therapy for IBD. Current anti-inflammatory, immunosuppressive, or biological treatment may induce and maintain remission, but not all patients respond to these treatments. Recent studies explored parasitic helminths as a novel modality of therapy due to their potent immunoregulatory properties in humans. Research using IBD animal models infected with a helminth or administered helminth-derived products such as excretory–secretory products has been promising, and helminth–microbiota interactions exert their anti-inflammatory effects by modulating the host immunity. Recent studies also indicate that evidence that helminth-derived metabolites may play a role in anticolitic effects. Thus, the helminth shows a potential benefit for treatment against IBD. Here we review the current feasibility of “helminth therapy” from the laboratory for application in IBD management.
Background
Therapeutic potential of helminth have been shown to have a protective effect on immune-mediated diseases such as Crohn's disease (CD), which is associated with increased production of T helper cell type 1. However, helminth therapy is unacceptable to patients due to side-effects and the fear of parasites. As helminths regulate the cellular immune responses through innate cells such as dendritic cells (DCs), cellular immunotherapy has been considered a therapeutic option to treat CD.
Methods
Bone marrow-dendritic cells were generated, enriched and treated with Trichinella spiralis muscle larval excretory/secretory products (Ts-MLES). DCs maturation was measured by flow cytometry and cytokine production of DCs were measured by ELISA. Colitis was generated by intrarectal administration of 2,4,6-trinitrobenzene sulfonic acid (TNBS) solution. For adoptive transfer, Ts-MLES treated-DCs injected intravenously 24 h prior to TNBS challenge. Disease activity index (DAI) including weight loss, diarrhea, and bloody stool were measured. Colon segments were stained with hematoxylin and eosin (H.E.) and periodic acid schiff (PAS) staining for histological damage scoring. The relative mRNA expression of cytokines in colon was analyzed by RT-PCR. Cytokine production in colon was measured by ELISA. Splenocytes were separated and cytokine profiles including Th1 (IFN-γ), Th2 (IL-4, IL-13), and Treg subsets (IL-10, TGF-β) were analyzed by flow cytometry.
Results
Ts-MLES regulated the maturation and cytokine production of DCs. Ts-MLES -DC ameliorated the severity of the TNBS-induced colitis. In the colon and the spleen, Ts-MLES-DC decreased IFN-γ (Th1) significantly and increased Th2 (IL-4, IL-13)- and Treg (IL-10, TGF-β)- related cytokines.
Conclusions
Ts-MLES-DC ameliorated the severity of the TNBS-induced colitis through decreasing IFN-γ. Ts-MLES-DC skewed the Th1-mediated response toward the Th2 type and regulatory T cell response.
