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      Parasite-Derived Proteins for the Treatment of Allergies and Autoimmune Diseases

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          Abstract

          The morbidity associated with atopic diseases and immune dysregulation disorders such as asthma, food allergies, multiple sclerosis, atopic dermatitis, type 1 diabetes mellitus, and inflammatory bowel disease has been increasing all around the world over the past few decades. Although the roles of non-biological environmental factors and genetic factors in the etiopathology have been particularly emphasized, they do not fully explain the increase; for example, genetic factors in a population change very gradually. Epidemiological investigation has revealed that the increase also parallels a decrease in infectious diseases, especially parasitic infections. Thus, the reduced prevalence of parasitic infections may be another important reason for immune dysregulation. Parasites have co-evolved with the human immune system for a long time. Some parasite-derived immune-evasion molecules have been verified to reduce the incidence and harmfulness of atopic diseases in humans by modulating the immune response. More importantly, some parasite-derived products have been shown to inhibit the progression of inflammatory diseases and consequently alleviate their symptoms. Thus, parasites, and especially their products, may have potential applications in the treatment of autoimmune diseases. In this review, the potential of parasite-derived products and their analogs for use in the treatment of atopic diseases and immune dysregulation is summarized.

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          Most cited references116

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          Allergy, parasites, and the hygiene hypothesis.

          The increase of allergic diseases in the industrialized world has often been explained by a decline in infections during childhood. The immunological explanation has been put into the context of the functional T cell subsets known as T helper 1 (TH1) and T helper 2 (TH2) that display polarized cytokine profiles. It has been argued that bacterial and viral infections during early life direct the maturing immune system toward TH1, which counterbalance proallergic responses of TH2 cells. Thus, a reduction in the overall microbial burden will result in weak TH1 imprinting and unrestrained TH2 responses that allow an increase in allergy. This notion is contradicted by observations that the prevalence of TH1-autoimmune diseases is also increasing and that TH2-skewed parasitic worm (helminth) infections are not associated with allergy. More recently, elevations of anti-inflammatory cytokines, such as interleukin-10, that occur during long-term helminth infections have been shown to be inversely correlated with allergy. The induction of a robust anti-inflammatory regulatory network by persistent immune challenge offers a unifying explanation for the observed inverse association of many infections with allergic disorders.
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            The Intestinal Microbiota Contributes to the Ability of Helminths to Modulate Allergic Inflammation

            Summary Intestinal helminths are potent regulators of their host’s immune system and can ameliorate inflammatory diseases such as allergic asthma. In the present study we have assessed whether this anti-inflammatory activity was purely intrinsic to helminths, or whether it also involved crosstalk with the local microbiota. We report that chronic infection with the murine helminth Heligmosomoides polygyrus bakeri (Hpb) altered the intestinal habitat, allowing increased short chain fatty acid (SCFA) production. Transfer of the Hpb-modified microbiota alone was sufficient to mediate protection against allergic asthma. The helminth-induced anti-inflammatory cytokine secretion and regulatory T cell suppressor activity that mediated the protection required the G protein-coupled receptor (GPR)-41. A similar alteration in the metabolic potential of intestinal bacterial communities was observed with diverse parasitic and host species, suggesting that this represents an evolutionary conserved mechanism of host-microbe-helminth interactions.
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              Trichuris suis therapy in Crohn's disease.

              Crohn's disease is common in highly industrialised Western countries where helminths are rare and uncommon in less developed areas of the world where most people carry worms. Helminths diminish immune responsiveness in naturally colonised humans and reduce inflammation in experimental colitis. Thus exposure to helminths may help prevent or even ameliorate Crohn's disease. The aim of the study was to determine the safety and possible efficacy of the intestinal helminth Trichuris suis in the treatment of patients with active Crohn's disease. Twenty nine patients with active Crohn's disease, defined by a Crohn's disease activity index (CDAI) > or =220 were enrolled in this open label study. All patients ingested 2500 live T suis ova every three weeks for 24 weeks, and disease activity was monitored by CDAI. Remission was defined as a decrease in CDAI to less than 150 while a response was defined as a decrease in CDAI of greater than 100. At week 24, 23 patients (79.3%) responded (decrease in CDAI >100 points or CDAI <150) and 21/29 (72.4%) remitted (CDAI <150). Mean CDAI of responders decreased 177.1 points below baseline. Analysis at week 12 yielded similar results. There were no adverse events. This new therapy may offer a unique, safe, and efficacious alternative for Crohn's disease management. These findings also support the premise that natural exposure to helminths such as T suis affords protection from immunological diseases like Crohn's disease.
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                Author and article information

                Contributors
                Journal
                Front Microbiol
                Front Microbiol
                Front. Microbiol.
                Frontiers in Microbiology
                Frontiers Media S.A.
                1664-302X
                07 November 2017
                2017
                : 8
                : 2164
                Affiliations
                [1] 1Department of Parasitology, Zhongshan School of Medicine, Sun Yat-sen University , Guangzhou, China
                [2] 2Key Laboratory of Tropical Disease Control (SYSU), Ministry of Education , Guangzhou, China
                [3] 3Provincial Engineering Technology Research Center for Diseases-Vectors Control , Guangzhou, China
                [4] 4Department of Pediatrics, The First Affiliated Hospital, Sun Yat-sen University , Guangzhou, China
                Author notes

                Edited by: Wei Hu, Fudan University, China

                Reviewed by: Magilé De La Caridad Fonseca, Instituto de Medicina Tropical “Pedro Kourí”, Cuba; George Grant, University of Aberdeen, United Kingdom

                *Correspondence: Xi Sun, sunxi2@ 123456mail.sysu.edu.cn

                These authors have contributed equally to this work and are co-first authors.

                This article was submitted to Infectious Diseases, a section of the journal Frontiers in Microbiology

                Article
                10.3389/fmicb.2017.02164
                5682104
                28197127
                fa8fc848-d84a-449a-97eb-a9e40eeeff54
                Copyright © 2017 Wu, Wang, Tang and Sun.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 10 June 2017
                : 20 October 2017
                Page count
                Figures: 0, Tables: 1, Equations: 0, References: 133, Pages: 13, Words: 0
                Funding
                Funded by: National Natural Science Foundation of China 10.13039/501100001809
                Award ID: 81572014
                Award ID: 81201309
                Award ID: 30972574
                Categories
                Microbiology
                Review

                Microbiology & Virology
                parasite,product,hygiene hypothesis,autoimmune disease,allergy
                Microbiology & Virology
                parasite, product, hygiene hypothesis, autoimmune disease, allergy

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