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Chandwaskar R, Dalal R, Gupta S, Sharma A, Parashar D, Kashyap VK, Sohal JS, Tripathi SK. Dysregulation of T cell response in the pathogenesis of inflammatory bowel disease. Scand J Immunol 2024; 100:e13412. [PMID: 39394898 DOI: 10.1111/sji.13412] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2023] [Revised: 08/26/2024] [Accepted: 09/17/2024] [Indexed: 10/14/2024]
Abstract
Inflammatory bowel disease (IBD), comprised of Crohn's disease (CD) and ulcerative colitis (UC), are gut inflammatory diseases that were earlier prevalent in the Western Hemisphere but now are on the rise in the East, with India standing second highest in the incidence rate in the world. Inflammation in IBD is a cause of dysregulated immune response, wherein helper T (Th) cell subsets and their cytokines play a major role in the pathogenesis of IBD. In addition, gut microbiota, environmental factors such as dietary factors and host genetics influence the outcome and severity of IBD. Dysregulation between effector and regulatory T cells drives gut inflammation, as effector T cells like Th1, Th17 and Th9 subsets Th cell lineages were found to be increased in IBD patients. In this review, we attempted to discuss the role of different Th cell subsets together with other T cells like CD8+ T cells, NKT and γδT cells in the outcome of gut inflammation in IBD. We also highlighted the potential therapeutic candidates for IBD.
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Affiliation(s)
- Rucha Chandwaskar
- Amity Institute of Microbial Technology (AIMT), Amity University Jaipur, Rajasthan, India
| | - Rajdeep Dalal
- Infection and Immunology Lab, Translational Health Science and Technology Institute, NCR-Biotech Science Cluster, 3rd Milestone, Faridabad-Gurgaon Expressway, Faridabad, Haryana, India
| | - Saurabh Gupta
- Centre for Vaccines and Diagnostic Research, GLA University, Mathura, Uttar Pradesh, India
| | - Aishwarya Sharma
- Sri Siddhartha Medical College and Research Center, Tumkur, Karnataka, India
| | - Deepak Parashar
- Department of Obstetrics and Gynecology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA
| | - Vivek K Kashyap
- Department of Immunology and Microbiology, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
- South Texas Center of Excellence in Cancer Research, School of Medicine, University of Texas Rio Grande Valley, McAllen, Texas, USA
| | - Jagdip Singh Sohal
- Centre for Vaccines and Diagnostic Research, GLA University, Mathura, Uttar Pradesh, India
| | - Subhash K Tripathi
- Center for Immunity and Immunotherapies and Program for Cell and Gene Therapy, Seattle Children's Research Institute, Seattle, Washington, USA
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Rajeev S, Li S, Leon-Coria A, Wang A, Kraemer L, Wang SJ, Boim A, Flannigan K, Shute A, Baggio CH, Callejas BE, MacNaughton WK, Finney CAM, McKay DM. Enteric tuft cells coordinate timely expulsion of the tapeworm Hymenolepis diminuta from the murine host by coordinating local but not systemic immunity. PLoS Pathog 2024; 20:e1012381. [PMID: 39083533 PMCID: PMC11290655 DOI: 10.1371/journal.ppat.1012381] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2023] [Accepted: 06/28/2024] [Indexed: 08/02/2024] Open
Abstract
Recognizing that enteric tuft cells can signal the presence of nematode parasites, we investigated whether tuft cells are required for the expulsion of the cestode, Hymenolepis diminuta, from the non-permissive mouse host, and in concomitant anti-helminthic responses. BALB/c and C57BL/6 mice infected with H. diminuta expelled the worms by 11 days post-infection (dpi) and displayed DCLK1+ (doublecortin-like kinase 1) tuft cell hyperplasia in the small intestine (not the colon) at 11 dpi. This tuft cell hyperplasia was dependent on IL-4Rα signalling and adaptive immunity, but not the microbiota. Expulsion of H. diminuta was slowed until at least 14 dpi, but not negated, in tuft cell-deficient Pou2f3-/- mice and was accompanied by delayed goblet cell hyperplasia and slowed small bowel transit. Worm antigen and mitogen evoked production of IL-4 and IL-10 by splenocytes from wild-type and Pou2f3-/- mice was not appreciably different, suggesting similar systemic immune reactivity to infection with H. diminuta. Wild-type and Pou2f3-/- mice infected with H. diminuta displayed partial protection against subsequent infection with the nematode Heligmosomoides bakeri. We speculate that, with respect to H. diminuta, enteric tuft cells are important for local immune events driving the rapidity of H. diminuta expulsion but are not critical in initiating or sustaining systemic Th2 responses that provide concomitant immunity against secondary infection with H. bakeri.
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Affiliation(s)
- Sruthi Rajeev
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - ShuHua Li
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - Aralia Leon-Coria
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
- Department of Biology, Faculty of Science, University of Calgary, Calgary, Alberta, Canada
| | - Arthur Wang
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - Lucas Kraemer
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - Susan Joanne Wang
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - Annaliese Boim
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - Kyle Flannigan
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Adam Shute
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
| | - Cristiane H. Baggio
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Blanca E. Callejas
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Wallace K. MacNaughton
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Constance A. M. Finney
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
- Department of Biology, Faculty of Science, University of Calgary, Calgary, Alberta, Canada
| | - Derek M. McKay
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Host-Parasite Interactions Program, University of Calgary, Calgary, Alberta, Canada
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3
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The Tapeworm Hymenolepis diminuta as an Important Model Organism in the Experimental Parasitology of the 21st Century. Pathogens 2022; 11:pathogens11121439. [PMID: 36558772 PMCID: PMC9784563 DOI: 10.3390/pathogens11121439] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2022] [Revised: 11/22/2022] [Accepted: 11/28/2022] [Indexed: 12/05/2022] Open
Abstract
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.
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Rodrigues VF, Camelo GMA, de Rezende MC, Maggi L, Silva JKAO, Rodrigues JGM, Araújo MSS, Martins-Filho OA, Negrão-Corrêa D. Infection by Strongyloides venezuelensis attenuates chronic colitis induced by Dextran Sodium Sulfate ingestion in BALB/c mice. Immunobiology 2021; 226:152129. [PMID: 34433129 DOI: 10.1016/j.imbio.2021.152129] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 07/02/2021] [Accepted: 08/11/2021] [Indexed: 10/20/2022]
Abstract
Inflammatory bowel diseases (IBD) are chronic health problems of difficult management and treatment. Epidemiological studies indicate an inverse association between helminth infections and IBD, and experimental data confirm that helminth infections modulate the severity of experimental acute colitis in mice. However, the effects of helminth infections on chronic colitis, which is clinically more relevant, have been poorly explored. Herein, we investigated whether Strongyloides venezuelensis infection in BALB/c mice can ameliorate chronic colitis induced by the ingestion of water containing 2.5% Dextran Sodium Sulfate (DSS) over three seven-day treatment cycles, with an interval of fourteen days between cycles. Infected-only, DSS-exposed-only, and non-exposed/uninfected experimental groups served as controls for comparing the severity of colitis and intestinal inflammation among different groups. Our data showed that S. venezuelensis infection in mice with DSS-induced chronic colitis reduced clinical signs, attenuated colon shortening and inflammation, and prevented mucus ablation. The modulatory effect was accompanied by a low concentration of IFN-γ, high concentrations of TGF-β, IL-22, and IL-33 in the colon, and a significant increase of the percentage of CD4+CD25+Foxp3+ Treg cells in the mesenteric lymph node (MLN). In conclusion, S. venezuelensis infection can reduce the severity of DSS-induced chronic colitis in mice possibly through the stimulation of Treg cells and modulatory cytokines, and induction of mucosal repair mechanisms.
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Affiliation(s)
| | | | | | - Laura Maggi
- Departamento de Parasitologia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | | | | | - Márcio Sobreira Silva Araújo
- Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou/FIOCRUZ - MG, Belo Horizonte, Minas Gerais, Brazil
| | - Olindo Assis Martins-Filho
- Grupo Integrado de Pesquisas em Biomarcadores, Instituto René Rachou/FIOCRUZ - MG, Belo Horizonte, Minas Gerais, Brazil
| | - Deborah Negrão-Corrêa
- Departamento de Parasitologia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil.
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Li S, Rajeev S, Wang A, McKay DM. Infection with Hymenolepis diminuta Blocks Colitis and Hastens Recovery While Colitis Has Minimal Impact on Expulsion of the Cestode from the Mouse Host. Pathogens 2021; 10:pathogens10080994. [PMID: 34451458 PMCID: PMC8401575 DOI: 10.3390/pathogens10080994] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 07/29/2021] [Accepted: 08/02/2021] [Indexed: 12/16/2022] Open
Abstract
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.
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Jirků M, Lhotská Z, Frgelecová L, Kadlecová O, Petrželková KJ, Morien E, Jirků-Pomajbíková K. Helminth Interactions with Bacteria in the Host Gut Are Essential for Its Immunomodulatory Effect. Microorganisms 2021; 9:microorganisms9020226. [PMID: 33499240 PMCID: PMC7910914 DOI: 10.3390/microorganisms9020226] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Revised: 01/20/2021] [Accepted: 01/21/2021] [Indexed: 12/14/2022] Open
Abstract
Colonization by the benign tapeworm, Hymenolepis diminuta, has been associated with a reduction in intestinal inflammation and changes in bacterial microbiota. However, the role of microbiota in the tapeworm anti-inflammatory effect is not yet clear, and the aim of this study was to determine whether disruption of the microflora during worm colonization can affect the course of intestinal inflammation. We added a phase for disrupting the intestinal microbiota using antibiotics to the experimental design for which we previously demonstrated the protective effect of H. diminuta. We monitored the immunological markers, clinical parameters, bacterial microbiota, and histological changes in the colon of rats. After a combination of colonization, antibiotics, and colitis induction, we had four differently affected experimental groups. We observed a different course of the immune response in each group, but no protective effect was found. Rats treated with colonization and antibiotics showed a strong induction of the Th2 response as well as a significant change in microbial diversity. The microbial results also revealed differences in the richness and abundance of some bacterial taxa, influenced by various factors. Our data suggest that interactions between the tapeworm and bacteria may have a major impact on its protective effect.
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Affiliation(s)
- Milan Jirků
- Biology Centre, Czech Academy of Sciences, Institute of Parasitology, Branišovská 31, 370 05 České Budějovice, Czech Republic; (Z.L.); (O.K.); (K.J.P.)
- Correspondence: (M.J.); (K.J.-P.); Tel.: +420-38-777-5470 (M.J.); +420-38-777-5470 (K.J.P.)
| | - Zuzana Lhotská
- Biology Centre, Czech Academy of Sciences, Institute of Parasitology, Branišovská 31, 370 05 České Budějovice, Czech Republic; (Z.L.); (O.K.); (K.J.P.)
- Department of Medical Biology, Faculty of Science, University of South Bohemia, Branišovská 31, 370 05 České Budějovice, Czech Republic
| | - Lucia Frgelecová
- Department of Pathology and Parasitology, University of Veterinary and Pharmaceutical Sciences Brno, Palackého tř. 1/3, 612 42 Brno, Czech Republic;
| | - Oldřiška Kadlecová
- Biology Centre, Czech Academy of Sciences, Institute of Parasitology, Branišovská 31, 370 05 České Budějovice, Czech Republic; (Z.L.); (O.K.); (K.J.P.)
| | - Klára Judita Petrželková
- Biology Centre, Czech Academy of Sciences, Institute of Parasitology, Branišovská 31, 370 05 České Budějovice, Czech Republic; (Z.L.); (O.K.); (K.J.P.)
- Institute of Vertebrate Biology, Czech Academy of Sciences, Květná, 8603 65 Brno, Czech Republic
| | - Evan Morien
- Department of Botany, University of British Columbia, 3156-6270 University Blvd., Vancouver, BC V6T 1Z4, Canada;
| | - Kateřina Jirků-Pomajbíková
- Biology Centre, Czech Academy of Sciences, Institute of Parasitology, Branišovská 31, 370 05 České Budějovice, Czech Republic; (Z.L.); (O.K.); (K.J.P.)
- Department of Medical Biology, Faculty of Science, University of South Bohemia, Branišovská 31, 370 05 České Budějovice, Czech Republic
- Correspondence: (M.J.); (K.J.-P.); Tel.: +420-38-777-5470 (M.J.); +420-38-777-5470 (K.J.P.)
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Rodrigues VF, Bahia MPS, Cândido NR, Moreira JMP, Oliveira VG, Araújo ES, Rodrigues Oliveira JL, Rezende MDC, Correa A, Negrão-Corrêa D. Acute infection with Strongyloides venezuelensis increases intestine production IL-10, reduces Th1/Th2/Th17 induction in colon and attenuates Dextran Sulfate Sodium-induced colitis in BALB/c mice. Cytokine 2018; 111:72-83. [PMID: 30118915 DOI: 10.1016/j.cyto.2018.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2017] [Revised: 07/26/2018] [Accepted: 08/06/2018] [Indexed: 12/15/2022]
Abstract
Helminth infection can reduce the severity of inflammatory bowel disease. However, the modulatory mechanisms elicited by helminth infection are not yet fully understood and vary depending on the experimental model. Herein we evaluated the effect of acute infection of BALB/c mice with Strongyloides venezuelensis on the clinical course of ulcerative colitis induced by Dextran Sulfate Sodium (DSS) treatment of these animals. For the experiments, S. venezuelensis-infected BALB/c mice were treated orally with 4% DSS solution for seven days. As controls, we used untreated S. venezuelensis infected, DSS-treated uninfected, and untreated/uninfected BALB/c mice. During DSS treatment, mice from the different groups were compared with regards to the clinical signs related to the severity of colitis and intestinal inflammation. Mice acutely infected with S. venezulensis and treated with DSS had reduced clinical score, shortening of the colon, and tissue inflammation. Moreover, DSS-treated and infected mice showed reduced IL-4, INF-γ, and IL-17 levels and increase of IL-10 production in the colon and/or in the supernatant of mesenteric lymph nodes cell cultures that resulted in lower eosinophil peroxidase and myeloperoxidase activity in colon homogenates, when compared with DSS-treated uninfected mice. DSS-treated infected mice also preserved the intestine architecture and had normal differentiation of goblet cells and mucus production in the colon mucosa. In conclusion, the data indicate that the clinical improvement reported in DSS-treated infected mice was accompanied by the lower production of Th1/Th2/Th17 pro-inflammatory cytokines, stimulation of IL-10, and induction of mucosal repair mechanisms.
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Affiliation(s)
- Vanessa Fernandes Rodrigues
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Márcia Paulliny Soares Bahia
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Núbia Rangel Cândido
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - João Marcelo Peixoto Moreira
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Vinicius Gustavo Oliveira
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Emília Souza Araújo
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Jailza Lima Rodrigues Oliveira
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Michelle de Carvalho Rezende
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Ary Correa
- Departments of Microbiology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil
| | - Deborah Negrão-Corrêa
- Departments of Parasitology, Biological Science Institute of the Federal University of Minas Gerais - UFMG, Belo Horizonte, MG, Brazil.
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The benign helminth Hymenolepis diminuta ameliorates chemically induced colitis in a rat model system. Parasitology 2018; 145:1324-1335. [DOI: 10.1017/s0031182018000896] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
AbstractThe tapeworm Hymenolepis diminuta is a model for the impact of helminth colonization on the mammalian immune system and a candidate therapeutic agent for immune mediated inflammatory diseases (IMIDs). In mice, H. diminuta protects against models of inflammatory colitis by inducing a strong type 2 immune response that is activated to expel the immature worm. Rats are the definitive host of H. diminuta, and are colonized stably and over long time periods without harming the host. Rats mount a mild type 2 immune response to H. diminuta colonization, but this response does not generally ameliorate colitis. Here we investigate the ability of different life cycle stages of H. diminuta to protect rats against a model of colitis induced through application of the haptenizing agent dinitrobenzene sulphonic acid (DNBS) directly to the colon, and monitor rat clinical health, systemic inflammation measured by TNFα and IL-1β, and the gut microbiota. We show that immature H. diminuta induces a type 2 response as measured by increased IL-4, IL-13 and IL-10 expression, but does not protect against colitis. In contrast, rats colonized with mature H. diminuta and challenged with severe colitis (two applications of DNBS) have lower inflammation and less severe clinical symptoms. This effect is not related the initial type 2 immune response. The gut microbiota is disrupted during colitis and does not appear to play an overt role in H. diminuta-mediated protection.
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Arai T, Lopes F, Shute A, Wang A, McKay DM. Young mice expel the tapeworm Hymenolepis diminuta and are protected from colitis by triggering a memory response with worm antigen. Am J Physiol Gastrointest Liver Physiol 2018; 314:G461-G470. [PMID: 29351392 PMCID: PMC5966750 DOI: 10.1152/ajpgi.00295.2017] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Infection with helminth parasites reduces the severity of concomitant inflammatory disease in adult mice. There is an alarming increase of inflammatory bowel disease (IBD) in children. It is important to determine whether helminth therapy would be of value in pediatric IBD and whether triggering immunological memory to the worm would be anticolitic. Three-week-old (young) and eight-week-old (adult) Balb/c mice were infected with H. diminuta, and infectivity and T helper 2 (Th2) immunity were assessed. Other mice received H. diminuta with or without a crude worm extract ( HdE) 28-42 days postinfection (dpi) with or without dinitrobenzene sulphonic acid [DNBS, 1.5 mg (young) or 3 mg (adults), ir], and colitis was assessed 72 h later. Infected young mice developed Th2 immunity and expelled H. diminuta; expulsion was delayed by ~2 days compared with adult mice. Colitis, as gauged by macroscopic disease and histopathology scores, was less severe in young mice infected 10 days, but not 8 days, before DNBS. Protection against DNBS-induced colitis was accompanied by an increased capacity to make interleukin (IL)-4 and IL-10. Mice infected with H. diminuta were not protected from DNBS-colitis when challenged 28 days later; however, injection of these mice with HdE coincident with DNBS resulted in less disease and increased splenic IL-4 and IL-10. Using a boost (500 μg HdE, 28 dpi) and repeat HdE (100 μg, 42 dpi) regimen with infected mice suppressed DNBS-colitis, as did adoptive transfer of splenic CD4+ T cells from infected mice with low-dose HdE challenge. Should these data translate to IBD, then helminth therapy could be of value in pediatric-onset IBD, and defining the antigen(s) that elicit antihelminth immunological memory could serve as an anticolitic approach in previously infected individuals. NEW & NOTEWORTHY This study demonstrates that juvenile mice are protected from colitis by infection with the tapeworm Hymenolepis diminuta and that using worm antigen to trigger an immunological memory response in previously infected mice can be used to limit the severity of colitis.
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Affiliation(s)
- Toshio Arai
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan, and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Fernando Lopes
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan, and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Adam Shute
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan, and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Arthur Wang
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan, and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Derek M. McKay
- Gastrointestinal Research Group and Inflammation Research Network, Department of Physiology and Pharmacology, Calvin, Joan, and Phoebe Snyder Institute for Chronic Disease, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
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Wang J, Goepfert C, Mueller N, Piersigilli A, Lin R, Wen H, Vuitton DA, Vuitton L, Mueller C, Gottstein B. Larval Echinococcus multilocularis infection reduces dextran sulphate sodium-induced colitis in mice by attenuating T helper type 1/type 17-mediated immune reactions. Immunology 2017; 154:76-88. [PMID: 29121394 PMCID: PMC5904711 DOI: 10.1111/imm.12860] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 10/27/2017] [Accepted: 10/29/2017] [Indexed: 12/13/2022] Open
Abstract
The tumour‐like growth of larval Echinococcus multilocularis tissue (causing alveolar echinococcosis, AE) is directly linked to the nature/orientation of the periparasitic host immune‐mediated processes. Parasite‐mediated immune suppression is a hallmark triggering infection outcome in both chronic human and murine AE. So far, little is known about secondary systemic immune effects of this pathogen on other concomitant diseases, e.g. endogenous gut inflammation. We examined the influence of E. multilocularis infection on murine dextran sodium sulphate (DSS) ‐induced colitis. At 3 months after E. multilocularis infection (chronic stage), the mice were challenged with 3% DSS in the drinking water for 5 days plus subsequently with tap water (alone) for another 4 days. After necropsy, fixed tissues/organs were sectioned and stained with haematoxylin & eosin for assessing inflammatory reactions. Cytokine levels were measured by flow cytometry and quantitative RT‐PCR. Colitis severity was assessed (by board‐certified veterinary pathologists) regarding (i) colon length, (ii) weight loss and (iii) a semi‐quantitative score of morphological changes. The histopathological analysis of the colon showed a significant reduction of DSS‐induced gut inflammation by concomitant E. multilocularis infection, which correlated with down‐regulation of T helper type 1 (Th1)/Th17 T‐cell responses in the colon tissue. Echinococcus multilocularis infection markedly reduced the severity of DSS‐induced gut inflammation upon down‐regulation of Th1/Th17 cytokine expression and attenuation of CD11b+ cell activation. In conclusion, E. multilocularis infection remarkably reduces DSS‐induced colitis in mice by attenuating Th1/Th17‐mediated immune reactions.
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Affiliation(s)
- Junhua Wang
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland.,State Key Laboratory Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Christine Goepfert
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Animal Pathology, COMPATH, University of Bern, Bern, Switzerland
| | - Norbert Mueller
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
| | - Alessandra Piersigilli
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Animal Pathology, COMPATH, University of Bern, Bern, Switzerland
| | - Renyong Lin
- State Key Laboratory Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Hao Wen
- State Key Laboratory Incubation Base of Xinjiang Major Diseases Research (2010DS890294) and Xinjiang Key Laboratory of Echinococcosis, First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang, China
| | - Dominique A Vuitton
- WHO-Collaborating Centre on Prevention and Treatment of Human Echinococcosis and French National Reference Centre on Alveolar Echinococcosis, University of Franche-Comté and University Hospital, Besançon, France
| | - Lucine Vuitton
- WHO-Collaborating Centre on Prevention and Treatment of Human Echinococcosis and French National Reference Centre on Alveolar Echinococcosis, University of Franche-Comté and University Hospital, Besançon, France.,Gastroenterology and Digestive Endoscopy, University Hospital, Besançon, France
| | - Christoph Mueller
- Institute of Pathology, Medical Faculty, University of Bern, Bern, Switzerland
| | - Bruno Gottstein
- Department of Infectious Diseases and Pathobiology, Vetsuisse Faculty, Institute of Parasitology, University of Bern, Bern, Switzerland
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11
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Pastille E, Frede A, McSorley HJ, Gräb J, Adamczyk A, Kollenda S, Hansen W, Epple M, Buer J, Maizels RM, Klopfleisch R, Westendorf AM. Intestinal helminth infection drives carcinogenesis in colitis-associated colon cancer. PLoS Pathog 2017; 13:e1006649. [PMID: 28938014 PMCID: PMC5627963 DOI: 10.1371/journal.ppat.1006649] [Citation(s) in RCA: 36] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2016] [Revised: 10/04/2017] [Accepted: 09/15/2017] [Indexed: 12/26/2022] Open
Abstract
Inflammatory bowel diseases (IBD) are chronic inflammatory disorders of the gastrointestinal tract, strongly associated with an increased risk of colorectal cancer development. Parasitic infections caused by helminths have been shown to modulate the host’s immune response by releasing immunomodulatory molecules and inducing regulatory T cells (Tregs). This immunosuppressive state provoked in the host has been considered as a novel and promising approach to treat IBD patients and alleviate acute intestinal inflammation. On the contrary, specific parasite infections are well known to be directly linked to carcinogenesis. Whether a helminth infection interferes with the development of colitis-associated colon cancer (CAC) is not yet known. In the present study, we demonstrate that the treatment of mice with the intestinal helminth Heligmosomoides polygyrus at the onset of tumor progression in a mouse model of CAC does not alter tumor growth and distribution. In contrast, H. polygyrus infection in the early inflammatory phase of CAC strengthens the inflammatory response and significantly boosts tumor development. Here, H. polygyrus infection was accompanied by long-lasting alterations in the colonic immune cell compartment, with reduced frequencies of colonic CD8+ effector T cells. Moreover, H. polygyrus infection in the course of dextran sulfate sodium (DSS) mediated colitis significantly exacerbates intestinal inflammation by amplifying the release of colonic IL-6 and CXCL1. Thus, our findings indicate that the therapeutic application of helminths during CAC might have tumor-promoting effects and therefore should be well-considered. Evidence from epidemiological studies indicates an inverse correlation between the incidence of certain immune-mediated diseases, including inflammatory bowel diseases, and exposure to helminths. As a consequence, helminth parasites were tested for treating IBD patients, resulting in clinical amelioration of the disease due to the induction of an immunosuppressive microenvironment. However, some infection–related cancers can be attributed to helminth infection, probably due to the generation of a microenvironment that might be conductive to the initiation and development of cancer. In the present study, we aimed to unravel the apparently controversial function of helminths in a mouse model of colitis-associated colon cancer. We show that helminth infection in the onset of colitis and colitis-associated colon cancer does not ameliorate colonic inflammation but activates intestinal immune cells that further facilitate tumor development. Therefore, a better understanding of mechanisms by which helminths modulate host immune responses in the gut should be defined precisely before application of helminths in autoimmune diseases like IBD.
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Affiliation(s)
- Eva Pastille
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Annika Frede
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Henry J. McSorley
- Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, United Kingdom
| | - Jessica Gräb
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Alexandra Adamczyk
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Sebastian Kollenda
- Institute for Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Duisburg, Germany
| | - Wiebke Hansen
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Matthias Epple
- Institute for Inorganic Chemistry and Center for Nanointegration Duisburg-Essen (CeNIDE), University of Duisburg-Essen, Duisburg, Germany
| | - Jan Buer
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
| | - Rick M. Maizels
- Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, United Kingdom
| | - Robert Klopfleisch
- Institute of Veterinary Pathology, Freie Universitaet Berlin, Berlin, Germany
| | - Astrid M. Westendorf
- Institute of Medical Microbiology, University Hospital Essen, University Duisburg-Essen, Essen, Germany
- * E-mail:
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12
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Wang M, Wu L, Weng R, Zheng W, Wu Z, Lv Z. Therapeutic potential of helminths in autoimmune diseases: helminth-derived immune-regulators and immune balance. Parasitol Res 2017; 116:2065-2074. [PMID: 28664463 DOI: 10.1007/s00436-017-5544-5] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Accepted: 06/21/2017] [Indexed: 12/22/2022]
Abstract
Helminths have accompanied human throughout history by releasing immune-evasion molecules that could counteract an aberrant immune response within the host. In the past decades, helminth infections are becoming less prevalent possibly due to the developed sanitation. Meanwhile, the incidence of autoimmune diseases is increasing, which cannot be exclusively explained by the changes of susceptibility genes. While the hygiene hypothesis casts light on the problem. The infections of helminths are believed to interact with and regulate human immunity with the byproduct of suppressing the autoimmune diseases. Thus, helminths are potential to treat or cure the autoimmune diseases. The therapeutic progresses and possible immune suppression mechanisms are illustrated in the review. The helminths that are studied most intensively include Heligmosomoides polygyrus, Hymenolepis diminuta, Schistosoma mansoni, Trichinella spiralis, and Trichuris suis. Special attentions are paid on the booming animal models and clinical trials that are to detect the efficiency of immune-modulating helminth-derived molecules on autoimmune diseases. These trials provide us with a prosperous clinical perspective, but the precise mechanism of the down-regulatory immune response remains to be clarified. More efforts are needed to be dedicated until these parasite-derived immune modulators could be used in clinic to treat or cure the autoimmune diseases under a standard management.
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Affiliation(s)
- Meng Wang
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China
| | - Linxiang Wu
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China
| | - Rennan Weng
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China
| | - Weihong Zheng
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China
| | - Zhongdao Wu
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China.,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China.,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China
| | - Zhiyue Lv
- Zhongshan School of Medicine, Sun Yat-sen University, 74 Zhongshan 2nd Road, Guangzhou, 510080, China. .,Key Laboratory of Tropical Disease Control (Sun Yat-sen University), Ministry of Education, Guangzhou, 510080, China. .,Provincial Engineering Technology Research Center for Biological Vector Control, Guangzhou, 510080, China.
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13
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Treatment with Cestode Parasite Antigens Results in Recruitment of CCR2+ Myeloid Cells, the Adoptive Transfer of Which Ameliorates Colitis. Infect Immun 2016; 84:3471-3483. [PMID: 27672083 DOI: 10.1128/iai.00681-16] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2016] [Accepted: 09/19/2016] [Indexed: 12/13/2022] Open
Abstract
Awareness of the immunological underpinnings of host-parasite interactions may reveal immune signaling pathways that could be used to treat inflammatory disease in humans. Previously we showed that infection with the rat tapeworm, Hymenolepis diminuta, used as a model helminth, or systemic delivery of worm antigen (HdAg) significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-induced colitis in mice. Extending these analyses, intraperitoneal injection of HdAg dose-dependently suppressed dextran sodium sulfate (DSS)-induced colitis, and this was paralleled by reduced gamma interferon (IFN-γ), interleukin-17 (IL-17), and tumor necrosis factor alpha (TNF-α) production and increased IL-10 production from mitogen-activated splenocytes. Treatment with HdAg resulted in a CCR2-dependent recruitment of CDllb+ F4/80+ Ly6Chi Gr-1lo monocyte-like cells into the peritoneum 24 h later that were predominantly programmed death ligand 1 (PD-L1) positive and CXCR2 negative. In vitro assays indicated that these cells were unable to suppress T cell proliferation but enhanced IL-10 and IL-4 production from activated T cells. Adoptive transfer of the HdAg-recruited monocytic cells into naive mice blocked DSS-induced colitis. These findings add to the variety of means by which treatment with parasitic helminth-derived antigens can ameliorate concomitant disease. A precise understanding of the mechanism(s) of action of HdAg and other helminth-derived antigens (and a parallel consideration of putative side effects) may lead to the development of novel therapies for human idiopathic disorders such as inflammatory bowel disease.
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14
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Loke P, Lim YAL. Helminths and the microbiota: parts of the hygiene hypothesis. Parasite Immunol 2015; 37:314-23. [PMID: 25869420 DOI: 10.1111/pim.12193] [Citation(s) in RCA: 54] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2014] [Accepted: 03/18/2015] [Indexed: 12/12/2022]
Abstract
In modern societies, diseases that are driven by dysregulated immune responses are increasing at an alarming pace, such as inflammatory bowel diseases and diabetes. There is an urgent need to understand these epidemiological trends, which are likely to be driven by the changing environment of the last few decades. There are complex interactions between human genetic factors and this changing environment that is leading to the increasing prevalence of metabolic and inflammatory diseases. Alterations to human gut bacterial communities (the microbiota) and lowered prevalence of helminth infections are potential environmental factors contributing to immune dysregulation. Helminths have co-evolved with the gut microbiota and their mammalian hosts. This three-way interaction is beginning to be characterized, and the knowledge gained may enable the design of new therapeutic strategies to treat metabolic and inflammatory diseases. However, these complex interactions need to be carefully investigated in the context of host genetic backgrounds to identify optimal treatment strategies. The complex nature of these interactions raises the possibility that only with highly personalized treatment, with knowledge of individual genetic and microbiota communities, will therapeutic interventions be successful for a majority of the individuals suffering from these complex diseases of immune dysregulation.
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Affiliation(s)
- P Loke
- Department of Microbiology, New York University School of Medicine, New York, NY, USA
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15
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Extraintestinal Helminth Infection Limits Pathology and Proinflammatory Cytokine Expression during DSS-Induced Ulcerative Colitis: A Role for Alternatively Activated Macrophages and Prostaglandins. BIOMED RESEARCH INTERNATIONAL 2015; 2015:563425. [PMID: 26090422 PMCID: PMC4450267 DOI: 10.1155/2015/563425] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/08/2014] [Revised: 10/14/2014] [Accepted: 10/20/2014] [Indexed: 01/05/2023]
Abstract
Chronic inflammation of the intestinal mucosa is characteristic of inflammatory bowel diseases such as ulcerative colitis and Crohn's disease. Helminth parasites have developed immunomodulatory strategies that may impact the outcome of several inflammatory diseases. Therefore, we investigated whether Taenia crassiceps infection is able to decrease the inflammatory effects of dextran sulfate sodium- (DSS-) induced ulcerative colitis in BALB/c and C57BL/6 mice. Preinfection significantly reduced the manifestations of DSS-induced colitis, as weight loss and shortened colon length, and decreased the disease activity index independently of the genetic background of the mice. Taenia infection decreased systemic levels of proinflammatory cytokines while increasing levels of IL-4 and IL-10, and the inflammatory infiltrate into the colon was also markedly reduced. RT-PCR assays from colon showed that T. crassiceps-infected mice displayed increased expression of Arginase-1 but decreased expression of iNOS compared to DSS-treated uninfected mice. The percentages of T regulatory cells were not increased. The adoptive transfer of alternatively activated macrophages (AAMФs) from infected mice into mice with DSS-induced colitis reduced the severity of colon inflammation. Administration of indomethacin abrogated the anticolitic effect of Taenia. Thus, T. crassiceps infection limits the pathology of ulcerative colitis by suppressing inflammatory responses mechanistically associated with AAMФs and prostaglandins.
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16
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McKay DM. Not all parasites are protective. Parasite Immunol 2015; 37:324-32. [DOI: 10.1111/pim.12160] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 11/09/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Derek M. McKay
- Department of Physiology and Pharmacology; Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases; Gastrointestinal Research Group and Inflammation Research Network; Cumming School of Medicine, University of Calgary; Calgary AB Canada
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17
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Reyes JL, Wang A, Fernando MR, Graepel R, Leung G, van Rooijen N, Sigvardsson M, McKay DM. Splenic B cells from Hymenolepis diminuta-infected mice ameliorate colitis independent of T cells and via cooperation with macrophages. THE JOURNAL OF IMMUNOLOGY 2014; 194:364-78. [PMID: 25452561 DOI: 10.4049/jimmunol.1400738] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
Helminth parasites provoke multicellular immune responses in their hosts that can suppress concomitant disease. The gut lumen-dwelling tapeworm Hymenolepis diminuta, unlike other parasites assessed as helminth therapy, causes no host tissue damage while potently suppressing murine colitis. With the goal of harnessing the immunomodulatory capacity of infection with H. diminuta, we assessed the putative generation of anti-colitic regulatory B cells following H. diminuta infection. Splenic CD19(+) B cells isolated from mice infected 7 [HdBc(7(d))] and 14 d (but not 3 d) previously with H. diminuta and transferred to naive mice significantly reduced the severity of dinitrobenzene sulfonic acid (DNBS)-, oxazolone-, and dextran-sodium sulfate-induced colitis. Mechanistic studies with the DNBS model, revealed the anti-colitic HdBc(7(d)) was within the follicular B cell population and its phenotype was not dependent on IL-4 or IL-10. The HdBc(7(d)) were not characterized by increased expression of CD1d, CD5, CD23, or IL-10 production, but did spontaneously, and upon LPS plus anti-CD40 stimulation, produce more TGF-β than CD19(+) B cells from controls. DNBS-induced colitis in RAG1(-/-) mice was inhibited by administration of HdBc(7(d)), indicating a lack of a requirement for T and B cells in the recipient; however, depletion of macrophages in recipient mice abrogated the anti-colitic effect of HdBc(7(d)). Thus, in response to H. diminuta, a putatively unique splenic CD19(+) B cell with a functional immunoregulatory program is generated that promotes the suppression of colitis dominated by TH1, TH2, or TH1-plus-TH2 events, and may do so via the synthesis of TGF-β and the generation of, or cooperation with, a regulatory macrophage.
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Affiliation(s)
- José L Reyes
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Arthur Wang
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Maria R Fernando
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Rabea Graepel
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Gabriella Leung
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada
| | - Nico van Rooijen
- Department of Molecular Cell Biology, Vrije Universiteit Amsterdam, 1081 BT Amsterdam, the Netherlands; and
| | - Mikael Sigvardsson
- Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping 581-85, Sweden
| | - Derek M McKay
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Joan and Phoebe Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta T2N 4N1, Canada;
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18
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Finlay CM, Walsh KP, Mills KHG. Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol Rev 2014; 259:206-30. [PMID: 24712468 DOI: 10.1111/imr.12164] [Citation(s) in RCA: 126] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Helminth parasites are highly successful pathogens, chronically infecting a quarter of the world's population, causing significant morbidity but rarely causing death. Protective immunity and expulsion of helminths is mediated by T-helper 2 (Th2) cells, type 2 (M2) macrophages, type 2 innate lymphoid cells, and eosinophils. Failure to mount these type 2 immune responses can result in immunopathology mediated by Th1 or Th17 cells. Helminths have evolved a wide variety of approaches for immune suppression, especially the generation of regulatory T cells and anti-inflammatory cytokines interleukin-10 and transforming growth factor-β. This is a very effective strategy for subverting protective immune responses to prolong their survival in the host but has the bystander effect of modulating immune responses to unrelated antigens. Epidemiological studies in humans have shown that infection with helminth parasites is associated with a low incidence of allergy/asthma and autoimmunity in developing countries. Experimental studies in mice have demonstrated that regulatory immune responses induced by helminth can suppress Th2 and Th1/Th17 responses that mediate allergy and autoimmunity, respectively. This has provided a rational explanation of the 'hygiene hypothesis' and has also led to the exploitation of helminths or their immunomodulatory products in the development of new immunosuppressive therapies for inflammatory diseases in humans.
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Affiliation(s)
- Conor M Finlay
- Immune Regulation Research Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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19
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Weinstock JV, Elliott DE. Helminth infections decrease host susceptibility to immune-mediated diseases. THE JOURNAL OF IMMUNOLOGY 2014; 193:3239-47. [PMID: 25240019 DOI: 10.4049/jimmunol.1400927] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Helminthic infection has become rare in highly industrialized nations. Concurrent with the decline in helminthic infection has been an increase in the prevalence of inflammatory disease. Removal of helminths from our environment and their powerful effects on host immunity may have contributed to this increase. Several helminth species can abrogate disease in murine models of inflammatory bowel disease, type 1 diabetes, multiple sclerosis, and other conditions. Helminths evoke immune regulatory pathways often involving dendritic cells, regulatory T cells, and macrophages that help to control disease. Cytokines, such as IL-4, IL-10, and TGF-β, have a role. Notable is the helminthic modulatory effect on innate immunity, which impedes development of aberrant adaptive immunity. Investigators are identifying key helminth-derived immune modulatory molecules that may have therapeutic usefulness in the control of inflammatory disease.
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Affiliation(s)
- Joel V Weinstock
- Division of Gastroenterology, Tufts Medical Center, Boston, MA 02111; and
| | - David E Elliott
- Division of Gastroenterology, University of Iowa, Iowa City, IA 52242
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20
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Wang X, Yang J, Cao Q, Tang J. Therapeutic efficacy and mechanism of water-soluble extracts of Banxiaxiexin decoction on BALB/c mice with oxazolone-induced colitis. Exp Ther Med 2014; 8:1201-1204. [PMID: 25187824 PMCID: PMC4151664 DOI: 10.3892/etm.2014.1890] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2014] [Accepted: 05/28/2014] [Indexed: 01/03/2023] Open
Abstract
The aim of the present study was to investigate the therapeutic effects of water-soluble extracts of Banxiaxiexin decoction, a classical traditional Chinese medicine formulation, on BALB/c mice with experimentally induced ulcerative colitis (UC). Water-soluble extracts of Banxiaxiexin decoction were intragastrically administered to BALB/c mice with oxazolone (OXA)-induced colitis. Sulfasalazine (SASP) was administered intragastrically to OXA-treated mice to establish the SASP group (positive control). Following drug administration, the disease activity index (DAI) and the histopathological inflammation score were recorded. In addition, the expression levels of interleukin (IL)-5 and IL-13 mRNA in the colonic tissue were determined by fluorescent quantitative polymerase chain reaction. The DAI and histopathological inflammation score of the model group were significantly greater compared with those of the control group, and the mRNA expression levels of IL-5 and IL-13 in the colonic tissue were also significantly higher in the model group compared with those in the control group. The intragastric administration of water-soluble extracts of Banxiaxiexin decoction significantly lowered the DAI and histopathological inflammation score. The mRNA expression levels of IL-5 and IL-13 in the colonic tissue were also significantly lowered. The therapeutic effect of Banxiaxiexin decoction was found to be comparable to that of SASP. In conclusion, the results from the present study demonstrate that water-soluble extracts of the traditional Chinese medicine formulation Banxiaxiexin decoction have a therapeutic effect on BALB/c mice with OXA-induced colitis.
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Affiliation(s)
- Xuewei Wang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Jinghui Yang
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Qin Cao
- Department of Gastroenterology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
| | - Jianmin Tang
- Department of Pathology, Putuo Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 200062, P.R. China
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21
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Heylen M, Ruyssers NE, Gielis EM, Vanhomwegen E, Pelckmans PA, Moreels TG, De Man JG, De Winter BY. Of worms, mice and man: an overview of experimental and clinical helminth-based therapy for inflammatory bowel disease. Pharmacol Ther 2014; 143:153-167. [PMID: 24603369 DOI: 10.1016/j.pharmthera.2014.02.011] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2014] [Accepted: 02/25/2014] [Indexed: 12/17/2022]
Abstract
The incidence of inflammatory and autoimmune disorders is highest in well-developed countries which is directly related to their higher hygienic standards: it is suggested that the lack of exposure to helminths contributes to the susceptibility for immune-related diseases. Epidemiological, experimental and clinical data support the idea that helminths provide protection against immune-mediated diseases such as inflammatory bowel disease (IBD). The most likely mechanism for the suppression of immune responses by helminths is the release of helminth-derived immunomodulatory molecules. This article reviews the experimental and clinical studies investigating the therapeutic potential of helminth-based therapy in IBD and also focuses on the current knowledge of its immunomodulatory mechanisms of action highlighting innate as well as adaptive immune mechanisms. Identifying the mechanisms by which these helminths and helminth-derived molecules modulate the immune system will help in creating novel drugs for the treatment of IBD and other disorders that result from an overactive immune response.
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Affiliation(s)
- Marthe Heylen
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Nathalie E Ruyssers
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Els M Gielis
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Els Vanhomwegen
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Paul A Pelckmans
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium; Antwerp University Hospital, Division of Gastroenterology & Hepatology, Antwerp, Belgium
| | - Tom G Moreels
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium; Antwerp University Hospital, Division of Gastroenterology & Hepatology, Antwerp, Belgium
| | - Joris G De Man
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium
| | - Benedicte Y De Winter
- Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium.
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22
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Induction of ulcerative colitis in mice influences the course of infection with the nematode Trichuris muris. J Helminthol 2014; 89:593-600. [PMID: 25007240 DOI: 10.1017/s0022149x14000558] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
The aim of this study was to assess the effect of infection with the nematode whipworm Trichuris muris on the course of chemically induced acute ulcerative colitis in CBA/J mice, a strain proven to be highly resistant to infection with T. muris. Each mouse was infected with 50 embryonated eggs of T. muris by oral gavage. Acute colitis was triggered by administering 4% dextran sulphate sodium (DSS) in the drinking water for nine consecutive days at different times after infection. Concurrent infection and DSS administration exacerbate the severity of the colitis while favouring the permanence of parasites in the intestine. The induction of ulcerative colitis from days 54 to 62 post-infection (p.i.), when all worms had been expelled, ameliorated the course of the inflammatory disease. When ulcerative colitis was triggered earlier on, from days 27 to 35 p.i., the beneficial effects on inflammatory events were clearly shown with signs of mucosal epithelization and regeneration as early as day 1 after DSS administration. Previous infections by T. muris therefore accelerate recovery from subsequently induced inflammatory bowel disease and such an effect assists the nematode to persist in the intestinal niche.
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Bhardwaj EK, Else KJ, Rogan MT, Warhurst G. Increased susceptibility to Trichuris muris infection and exacerbation of colitis in Mdr1a-/- mice. World J Gastroenterol 2014; 20:1797-1806. [PMID: 24587657 PMCID: PMC3930978 DOI: 10.3748/wjg.v20.i7.1797] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2013] [Revised: 10/12/2013] [Accepted: 11/19/2013] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the influence of Trichuris muris (T. muris) infection in a mouse model of genetic susceptibility to inflammatory bowel disease, Mdr1a-/-.
METHODS: Mdr1a-/- mice were housed under specific pathogen free conditions to slow the development of colitis and compared to congenic FVB controls. Mice were infected with approximately 200 embryonated ova from T. muris and assessed for worm burden and histological and functional markers of gut inflammation on day 19 post infection.
RESULTS: Mdr1a-/- mice exhibited a marked increase in susceptibility to T. muris infection with a 10-fold increase in colonic worm count by day 19 pi compared to FVB controls. Prior to infection, Mdr1a-/- exhibited low-level mucosal inflammation with evidence of an enhanced Th1 environment. T. muris infection accelerated the progression of colitis in Mdr1a-/- as evidenced by marked increases in several indicators including histological damage score, mucosal CD4+ T-cell and DC infiltration and dramatically increased production of pro-inflammatory cytokines.
CONCLUSION: These data provide further evidence of the complex interaction between T. muris and an inflammatory bowel disease (IBD)-susceptible host which may have relevance to the application of helminth therapy in the treatment of human IBD.
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Preventive Effect of TU-100 on a Type-2 Model of Colitis in Mice: Possible Involvement of Enhancing Adrenomedullin in Intestinal Epithelial Cells. Gastroenterol Res Pract 2013; 2013:384057. [PMID: 24348533 PMCID: PMC3852085 DOI: 10.1155/2013/384057] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/20/2013] [Revised: 10/01/2013] [Accepted: 10/07/2013] [Indexed: 12/29/2022] Open
Abstract
Purpose. Crohn's disease (CD) and ulcerative colitis (UC), the two major forms of inflammatory bowel disease (IBD), have histopathologically and immunologically different characteristics. We previously reported that a traditional Japanese medicine, daikenchuto (TU-100), ameliorated a trinitrobenzenesulfonic acid- (TNBS-) induced type-1 model colitis exhibiting histopathological features of CD through adrenomedullin (ADM) enhancement. Our current aims were to examine whether TU-100 ameliorates a type-2 model colitis that histologically resembles UC and identify the active ingredients. Methods. TU-100 was administered orally to mice with oxazolone- (OXN-) induced type-2 model colitis. The morbidity was evaluated by body weight loss and the macroscopic score of colonic lesions. ADM was quantified using an EIA kit. Results. TU-100 prevented weight loss and colon ulceration. ADM production by intestinal epithelial cells was increased by TU-100 addition. Screening to identify active ingredients showed that [6]-shogaol and hydroxy α -sanshool enhanced ADM production. Conclusions. TU-100 exerted a protective effect in OXN-induced type-2 model colitis, indicating that TU-100 may be a beneficial agent for treatment of UC.
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Low D, Nguyen DD, Mizoguchi E. Animal models of ulcerative colitis and their application in drug research. Drug Des Devel Ther 2013; 7:1341-57. [PMID: 24250223 PMCID: PMC3829622 DOI: 10.2147/dddt.s40107] [Citation(s) in RCA: 105] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed.
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Affiliation(s)
- Daren Low
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Deanna D Nguyen
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for the Study of inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Emiko Mizoguchi
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for the Study of inflammatory Bowel Disease, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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26
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Low D, Nguyen DD, Mizoguchi E. Animal models of ulcerative colitis and their application in drug research. DRUG DESIGN DEVELOPMENT AND THERAPY 2013. [PMID: 24250223 DOI: 10.2147/dddt.s40107.ecollection] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The specific pathogenesis underlying inflammatory bowel disease is complex, and it is even more difficult to decipher the pathophysiology to explain for the similarities and differences between two of its major subtypes, Crohn's disease and ulcerative colitis (UC). Animal models are indispensable to pry into mechanistic details that will facilitate better preclinical drug/therapy design to target specific components involved in the disease pathogenesis. This review focuses on common animal models that are particularly useful for the study of UC and its therapeutic strategy. Recent reports of the latest compounds, therapeutic strategies, and approaches tested on UC animal models are also discussed.
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Affiliation(s)
- Daren Low
- Gastrointestinal Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
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27
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Graepel R, Leung G, Wang A, Villemaire M, Jirik FR, Sharkey KA, McDougall JJ, McKay DM. Murine autoimmune arthritis is exaggerated by infection with the rat tapeworm, Hymenolepis diminuta. Int J Parasitol 2013; 43:593-601. [PMID: 23583716 DOI: 10.1016/j.ijpara.2013.02.006] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Revised: 02/15/2013] [Accepted: 02/19/2013] [Indexed: 01/21/2023]
Abstract
Infection with helminth parasites triggers strong and stereotypic immune responses in humans and mice, which can protect against specific experimentally-induced autoimmune diseases. We have shown that infection with the rat tapeworm, Hymenolepis diminuta, confers a protective effect on FCA-induced joint inflammation. Here, we investigated the effect of a prophylactic infection with H. diminuta on the K/BxN-serum model of polyarthritis in BALB/c mice. Mice were infected with 10 cysticercoids of H. diminuta by oral gavage and 8 days later arthritis was induced by i.p. injection of K/BxN arthritogenic serum. Joint swelling and pain measurements were recorded throughout a 13 day time course. At necropsy, joints and blood serum were collected. K/BxN-treated mice developed joint inflammation in the front paws, hind paws and knees as shown by increased swelling, mechanical allodynia and myeloperoxidase activity. Mice infected with H. diminuta had more severe disease, with increased eosinophil peroxidase activity in their paws and greater inflammatory infiltrate and synovitis in the knee joints. Hymenolepis diminuta-infected mice displayed significant increases in serum levels of C5a and mast cell protease-1 compared with K/BxN-serum only treatment, the latter being indicative of mast cell activation. In contrast to the protective effect of infection with H. diminuta in FCA-induced monoarthritis, infection with this helminth exacerbated K/BxN serum-induced polyarthritis in BALB/c mice. This correlated with increases in C5a and mast cell activation: factors critical in the development of K/BxN-induced arthritis. Thus, while data accumulate from animal models showing that infection with helminth parasites may be beneficial for a variety of auto-inflammatory diseases, our findings demonstrate the potential for helminths to exacerbate disease. Hence care is needed when helminth therapy is translated into a clinical setting.
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Affiliation(s)
- Rabea Graepel
- Gastrointestinal Research Group, Department of Physiology & Pharmacology, The Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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28
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Khan AR, Fallon PG. Helminth therapies: translating the unknown unknowns to known knowns. Int J Parasitol 2013; 43:293-9. [PMID: 23291459 DOI: 10.1016/j.ijpara.2012.12.002] [Citation(s) in RCA: 58] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2012] [Revised: 12/01/2012] [Accepted: 12/03/2012] [Indexed: 12/26/2022]
Abstract
The use of live helminth infections is currently in clinical trials as a novel approach for the treatment of a range of allergic and autoimmune diseases. This rapid progression from observational studies some 20 years ago to helminth clinical trials can be attributed to huge advances in not just pre-clinical and clinical evidence, pertaining to the efficacy of these parasites in unrelated diseases, but also a greater understanding of the complex immunological mechanisms that underpin these effects. Helminths have exerted significant evolutionary selective pressures on the host immune genome or "immunome". Studies on helminths were pivotal in a paradigm shift in immunology with recent discoveries of a number of novel immune cell populations. Critically, these new discoveries highlight the need to further understand the underlying mechanism behind the desirable therapeutic effects that helminths offer. With these unknown unknowns there is the distinct possibility that a true, fundamental modus operandi for helminth therapy will arrive long after it has been established in the clinic.
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Affiliation(s)
- Adnan R Khan
- Trinity Biomedical Sciences Institute, School of Medicine, Trinity College Dublin, and National Children's Research Centre, Our Lady's Children's Hospital, Ireland
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29
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Ortiz-Flores AM, Ledesma-Soto Y, Calleja EA, Rodríguez-Sosa M, Juárez I, Terrazas LI. Taenia crassiceps infection does not influence the development of experimental rheumatoid arthritis. BIOMED RESEARCH INTERNATIONAL 2012; 2013:316980. [PMID: 23509709 PMCID: PMC3591108 DOI: 10.1155/2013/316980] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/14/2012] [Accepted: 10/12/2012] [Indexed: 12/01/2022]
Abstract
It was previously reported by our group that infection with Taenia crassiceps reduces incidence and severity of inflammatory and autoimmune experimental diseases like type 1 diabetes and experimental autoimmune encephalomyelitis. In this research, we set out to study whether infection with T. crassiceps would affect the development of experimental rheumatoid arthritis (RA). We found that mice infected with the parasite and induced with experimental RA showed similar clinical scores as the noninfected experimental RA group; systemic cytokines were not affected while anti-CII Abs were higher in the infected group. Histological evaluation showed damage in both infected and noninfected experimental RA-induced groups and although some surface molecules such as PDL-2 and MR which are associated with immunomodulatory mechanisms were upregulated in the infected and RA-induced group as compared to the noninfected RA group, they did not exert any changes in the outcome of experimental RA. Thus, we determined that infection with T. crassiceps does not influence the outcome of experimental RA.
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MESH Headings
- Animals
- Arthritis, Experimental/complications
- Arthritis, Experimental/immunology
- Arthritis, Experimental/parasitology
- Arthritis, Rheumatoid/complications
- Arthritis, Rheumatoid/immunology
- Arthritis, Rheumatoid/parasitology
- Autoimmune Diseases/immunology
- Cell Membrane/metabolism
- Disease Models, Animal
- Immunoglobulin G/immunology
- Inflammation
- Interferon-gamma/metabolism
- Macrophages, Peritoneal/immunology
- Male
- Mice
- Mice, Inbred BALB C
- Mice, Transgenic
- Taenia
- Taeniasis/complications
- Taeniasis/immunology
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Affiliation(s)
- Aaxin M. Ortiz-Flores
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Yadira Ledesma-Soto
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Elsa A. Calleja
- Carrera de Medicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Miriam Rodríguez-Sosa
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Imelda Juárez
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
| | - Luis I. Terrazas
- Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México (UNAM), 54090 Tlalnepantla, MEX, Mexico
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Abstract
Modern hygienic lifestyles are associated with the emergence of inflammatory bowel disease (IBD) which now afflicts millions of people in highly-developed countries. Meticulous hygiene interrupts conduits of transmission required for ubiquitous exposure to parasitic worms (helminths). We proposed that loss of exposure to helminths permits development of IBD. Early clinical trials suggested that exposure to helminths such as Trichuris suis or Necator americanus can improve IBD. Over the last several years, processes to "medicinalize"T. suis have been developed and use of this helminth is now being studied in large multi-center clinical trials. Concurrently, we and others have identified some of the immune regulatory mechanisms elicited by helminth exposure that suppress inappropriate intestinal inflammation. These efforts could soon result in new therapies for patients with IBD.
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Affiliation(s)
- Joel V Weinstock
- Division of Gastroenterology, Tufts Medical Center, Boston, MA, USA.
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31
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Hernandez JLR, Leung G, McKay DM. Cestode regulation of inflammation and inflammatory diseases. Int J Parasitol 2012; 43:233-43. [PMID: 23058631 DOI: 10.1016/j.ijpara.2012.09.005] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2012] [Revised: 09/11/2012] [Accepted: 09/12/2012] [Indexed: 12/13/2022]
Abstract
Helminth parasites are masters of immune regulation; a likely prerequisite for long-term survival by circumventing their hosts' attempt to eradicate them. From a translational perspective, knowledge of immune events as a response to infection with a helminth parasite could be used to reduce the intensity of unwanted inflammatory reactions. Substantial data have accumulated showing that inflammatory reactions that promote a variety of auto-inflammatory diseases are dampened as a consequence of infection with helminth parasites, via either the mobilization of an anti-worm spectrum of immune events or by the direct effect of secretory/excretory bioactive immunomodulatory molecules released from the parasite. However, many issues are outstanding in the definition of the mechanism(s) by which infection with helminth parasites can affect the outcome, positively or negatively, of concomitant disease. We focus on a subgroup of this complex group of metazoan parasites, the cestodes, summarizing studies from rodent models that illustrate if, and by what mechanisms, infection with tapeworms ameliorate or exaggerate disease in their host. The ability of infection with cestodes, or other classes of helminth, to worsen a disease course or confer susceptibility to intracellular pathogens should be carefully considered in the context of 'helminth therapy'. In addition, poorly characterised cestode extracts can regulate murine and human immunocyte function, yet the impact of these in the context of autoimmune or allergic diseases is poorly understood. Thus, studies with cestodes, as representative helminths, have helped cement the concept that infection with parasitic helminths can inhibit concomitant disease; however, issues relating to long-term effects, potential side-effects, mixed pathogen infections and purification of immunomodulatory molecules from the parasite remain as challenges that need to be addressed in order to achieve the use of helminths as anti-inflammatory agents for human diseases.
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Affiliation(s)
- Jose-Luis Reyes Hernandez
- Gastrointestinal Research Group, Department of Physiology and Pharmacology, Calvin, Phoebe and Joan Snyder Institute for Chronic Diseases, University of Calgary, Calgary, Alberta, Canada
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Camelo A, Barlow JL, Drynan LF, Neill DR, Ballantyne SJ, Wong SH, Pannell R, Gao W, Wrigley K, Sprenkle J, McKenzie ANJ. Blocking IL-25 signalling protects against gut inflammation in a type-2 model of colitis by suppressing nuocyte and NKT derived IL-13. J Gastroenterol 2012; 47:1198-211. [PMID: 22539101 PMCID: PMC3501170 DOI: 10.1007/s00535-012-0591-2] [Citation(s) in RCA: 100] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2011] [Accepted: 03/22/2012] [Indexed: 02/04/2023]
Abstract
BACKGROUND Interleukin-25 (IL-25) is a potent activator of type-2 immune responses. Mucosal inflammation in ulcerative colitis is driven by type-2 cytokines. We have previously shown that a neutralizing anti-IL-25 antibody abrogated airways hyperreactivity in an experimental model of lung allergy. Therefore, we asked whether blocking IL-25 via neutralizing antibodies against the ligand or its receptor IL-17BR could protect against inflammation in an oxazolone-induced mouse model of colitis. METHODS Neutralizing antibodies to IL-25 or IL-17BR were administered to mice with oxazolone-induced colitis, a model of ulcerative colitis. The disease onset was evaluated by weight loss and degree of colon ulceration. Also, lamina propria and mesenteric lymph node (MLN) infiltrates were assessed for mucosal inflammation and cultured in vitro to determine cytokine production. RESULTS We found that in oxazolone colitis IL-25 production derives from intestinal epithelial cells and that IL-17BR(+) IL-13-producing natural killer T (NKT) cells and nuocytes drive the intestinal inflammation. Blocking IL-25 signalling considerably improved the clinical aspects of the disease, including weight loss and colon ulceration, and resulted in fewer nuocytes and NKT cells infiltrating the mucosa. The improved pathology correlated with a decrease in IL-13 production by lamina propria cells, a decrease in the production of other type-2 cytokines by MLN cells, and a decrease in blood eosinophilia and IgE. CONCLUSION IL-25 plays a pro-inflammatory role in the oxazolone colitis model, and neutralizing antibodies to IL-25 or IL-17BR can slow the ongoing inflammation in this disease. Because this model mimics aspects of human ulcerative colitis, these antibodies may represent potential therapeutics for reducing gut inflammation in patients.
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Affiliation(s)
- Ana Camelo
- MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK
| | | | | | - Daniel R. Neill
- Present Address: Department of Clinical Infection, Microbiology and Immunology, Institute of Infection and Global Health, University of Liverpool, Liverpool, L69 7BE UK
| | | | - See Heng Wong
- Present Address: MedImmune, Milstein Building, Granta Park, Cambridge, CB1 6GH UK
| | - Richard Pannell
- MRC Laboratory of Molecular Biology, Hills Road, Cambridge, UK
| | - Wei Gao
- Centocor Research and Development, a division of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 145 King of Prussia Road, Radnor, PA 19087 USA
| | - Keely Wrigley
- Centocor Research and Development, a division of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 145 King of Prussia Road, Radnor, PA 19087 USA
| | - Justin Sprenkle
- Centocor Research and Development, a division of Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 145 King of Prussia Road, Radnor, PA 19087 USA
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33
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Helminth parasites and the modulation of joint inflammation. J Parasitol Res 2011; 2011:942616. [PMID: 21584243 PMCID: PMC3092582 DOI: 10.1155/2011/942616] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2010] [Accepted: 02/14/2011] [Indexed: 01/16/2023] Open
Abstract
There is an urgent need to develop better therapeutics for autoimmune and autoinflammatory diseases, of which musculoskeletal disorders such as rheumatoid arthritis are particularly prevalent and debilitating. Helminth parasites are accomplished masters at modifying their hosts' immune activity, and so attention has focused on rodent-helminth model systems to uncover the workings of the mammalian immune response to metazoan parasites, with the hope of revealing molecules and/or mechanisms that can be translated into better treatments for human autoimmune and idiopathic disorders. Substantial proof-of-principal data supporting the concept that infection with helminth parasites can reduce the severity of concomitant disease has been amassed from models of mucosal inflammation. Indeed, infection with helminth parasites has been tried as a therapy in inflammatory bowel disease, and there are case reports relating to other conditions (e.g., autism); however, the impact of infection with parasitic helminths on musculoskeletal diseases has not been extensively studied. Here, we present the view that such a strategy should be applied to the amelioration of joint inflammation and review the literature that supports this contention.
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