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Helminthic Therapy: Improving Mucosal Barrier Function

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Helminthic Therapy: Improving Mucosal Barrier Function TREPAR-1107; No. of Pages 8 Review Helminthic therapy: improving mucosal barrier function 1 2 3 Martin J. Wolff , Mara J. Broadhurst and P’ng Loke 1 Division of Gastroenterology, Department of Medicine, New York University School of Medicine, New York, NY 10010, USA 2 Division of Experimental Medicine, Department of Medicine, University of California San Francisco, San Francisco, CA 94110, USA 3 Division of Medical Parasitology, Department of Microbiology, New York University School of Medicine, NY 10010, USA The epidemiology of autoimmune diseases and hel- increased goblet cell hyperplasia and mucus production, minth infections led to suggestions that helminths could and increased turnover of intestinal epithelial cells [3]. We improve inflammatory conditions, which was then test- propose that these alterations to mucosal barrier function ed using animal models. This has translated to clinical in the gut play a protective role against pathology associ- investigations aimed at the safe and controlled reintro- ated with inflammatory bowel diseases (IBD) (especially duction of helminthic exposure to patients suffering ulcerative colitis, UC) and may potentially be as mecha- from autoimmune diseases (so-called ‘helminthic thera- nistically important as immune regulation in modulating py’) in an effort to mitigate the inflammatory response. the inflammatory response. In this review, we summarize the results of recent clinical trials of helminthic therapy, with particular attention to Clinical trials with Trichuris suis ova mechanisms of action. Whereas previous reviews have Therapeutic infection with the pig whipworm Trichuris emphasized immune regulatory mechanisms activated suis was first investigated in 2003 in an exploratory open- by helminths, we propose that enhancement of mucosal label study of seven patients with IBD [4]. T. suis ova (TSO) barrier function may have an equally important role in are considered to be ideal agents because they produce self- improving conditions of inflammatory bowel diseases. limited colonization in humans and remain isolated to the gastrointestinal tract. Additionally, ova can be obtained Rationale for helminthic therapy under pathogen-free conditions, can be stored for approxi- Based on the epidemiology of autoimmune diseases, envi- mately 2 years and any unexpected long-term colonization ronmental factors such as helminth infection have long can be effectively eradicated with short courses of oral been part of the hygiene hypothesis to explain why auto- antihelminthic agents. The ova contain the infective J1 immunity may be less prevalent in the developing world. larval stage that has developed from a single cell within the Subsequently, helminth infections in animal models have egg, which is excreted from the feces of infected animals. been shown to improve the conditions of certain inflamma- The larvae hatch from the eggs in the cecum and will tory diseases, leading to clinical trials of ‘helminthic ther- penetrate the mucosa before undergoing several molts to apy’ (Table 1). Helminths are multicellular metazoan mature into the adult stage that can start shedding eggs in organisms with the potential to cause significant tissue pigs. In humans, the lifecycle is attenuated and the larvae injury as they mature, migrate and feed within the host. do not fully mature into adults. Due to effective immune evasion strategies, these para- Subsequent clinical trials of TSO reported significant sites can persist in the host for many years. The immune improvement in patient responses for both UC and Crohn’s response that optimizes host fitness must be well-adapted disease with essentially no adverse effects [5–8]. In a for: (i) expelling large multicellular pathogens; (ii) wound landmark randomized, placebo-controlled, double-blind healing and tissue repair and (iii) mitigating inflammatory study of 54 subjects with moderate to severe UC, subjects pathology associated with chronic infection. These mecha- in the treatment group ingested 2500 TSO every 2 weeks nisms are encompassed within the TH2 immune response for a total of 12 weeks [5]. Subjects were evaluated with the elicited by helminth infection and the activation of regula- Ulcerative Colitis Disease Activity Index (UCDAI) at week tory networks that dampen effector T cell responses [1,2]. 0 and week 12 (which requires inspection of the colonic Elements of the TH2 immune response, as well as the mucosa by endoscopy) in addition to biweekly assessment induction of regulatory T cells, may contribute in varying with a symptom-based index [9]. After 12 weeks of therapy, degrees to the benefits of helminth infection in different 43.3% of the individuals treated with TSO had improved autoimmune and inflammatory disease settings. The type symptoms (defined as a decrease in UCDAI of 4 points) 2 immune response triggered by gastrointestinal hel- compared to 16.7% in the placebo group, which was a + minths includes cytokines produced by CD4 TH2 cells statistically significant response rate. Furthermore, and innate lymphocytes (e.g. IL-4, IL-5 and IL-13), activa- TSO-treated subjects reported significant improvement tion of alternatively activated macrophages and mast cells, in their symptoms (compared with placebo) as early as week 6. This was the first trial to define a subgroup of Corresponding author: Loke, P. ([email protected]). relatively treatment-refractory patients who responded to Keywords: helminthic therapy; TH2 response; immune regulation; mucosal immu- nity; mucus; IL-4; IL-22; microbiome. helminthic therapy in a controlled setting. There was a 1471-4922/$ – see front matter ß 2012 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2012.02.008 Trends in Parasitology xx (2012) 1–8 1 TREPAR-1107; 2 Review Table 1. Selected clinical studies of helminthic therapy in human disease Year of Patient population Number of Trial design Clinical assessment measures Main observations publication (institution) subjects 2003 [4] Crohn’s disease and Initial phase: Open-label Phase I pilot Safety assessment No adverse events observed ulcerative colitis 4 (CD) Initial phase: Remission: After single dose of TSO in CD: 75% achieved remission, No. (University of Iowa) 3 (UC) 2500 TSO PO  1 CDAI < 150 66% relapse rate by week 12 Maintenance Clinical monitoring q2 week IBDQ >170 After single dose of TSO in UC: 100% achieve remission, of phase:  12 weeks SCCAI < 4 33% relapse rate by week 12 Pages 2 (CD) Maintenance phase: Maintenance phase: 100% achieved remission with 2 (UC) 2500 TSO q3week  28 weeks triweekly dosing for > 28 weeks 8 2005 [8] Active Crohn’s disease 29 24-week open-label Response: CDAI decrease >100 At week 12, 75.9% responded, 65.5% remitted (CDAI > 220) Phase I study Remission: CDAI <150 At week 24, 79.3% responded, 72.% remitted (University of Iowa) 2500 TSO PO q2weeks 2005 [5] Moderate-severe 54 12-week randomized Response: UCDAI < 4 At week 12, 43.3% (TSO) vs. 16.7% (PBO) ulcerative colitis double-blind placebo-controlled trial Remission: UCDAI < 2 At week 12, nonsignificant differences in remission rates (University of Iowa) 2500 TSO PO q2weeks observed between treatment groups 2006 [32] Crohn’s disease 9 45-week open-label POC study Response: CDAI remained unchanged until week 17 (Townsville Hospital, 25–50 NA L3i SC at 0 and 27 weeks CDAI < 150 Four week cumulated CDAI scores decreased after 20 Australia) IBDQ > 170 weeks (mean 141 v 87) IBDQ improved after 20 weeks (mean 151 v 179) Adverse events included anemia, painful transient enteropathy and peripheral eosinophilia 2009 [30] AMP-responsive 32 16-week randomized double-blind Change in provocation dose of inhaled AMP No significant differences in mean airway responsiveness Asthma placebo-controlled study required to reduced forced expiratory (PD20AMP), asthma control or allergen skin testing were 10 NA L3i SC volume in 1 s by 20% (PD20AMP) observed 2010 [15] Treatment-naı¨ve 5 Phase I baseline vs. treatment study Neurological function (MSFC and EDSS) No adverse events observed relapsing remitting 2500 TSO PO q2weeks  3 months Gadolinium-enhancing lesions on MRI No significant change observed in baseline versus multiple sclerosis Immunologic assessments (e.g. serum treatment neurological functioning (University of T. suis specific IgG1 and IgA) Mean number of new gadolinium-enhancing MRI lesions Wisconsin) (n–Gd+) decreased (6.6 at baseline to 2.0 at 3 months). The number of n–Gd+ rose to 5.8 2 months after TSO discontinued. 2010 [10] Allergic rhinitis 100 27-week randomized double-blind Symptom severity score of allergic rhinitis Treatment with TSO caused transient diarrhea peaking at (Statens Serum placebo-controlled trial Skin prick testing day 41 in 33% of participants (placebo, 2%) Institut and University 2500 TSO PO q2weeks  25 weeks Immunologic assessments (e.g. serum No significant change in symptom scores, total histamine, of Copenhagen, T. suis-specific IgA and IgE, serum grass- grass-specific IgE or diameter of wheal reaction in skin Trends Denmark) specific IgE and total histamine) prick testing with several allergens observed 2010 [63] Ulcerative colitis 1 Case study Mucus production Helminth exposure associated with clinical remission and (University of 1500 Trichuris trichiura PO ova ad lib Mucosal gene expression mucosal healing in San Francisco) for 5 years Flow cytometric analysis of effector Helminth exposure associated with increased IL–17+IL–22+ Parasitology T helper cell cytokine production cells compared to episodes of colitis Helminth exposure associated with genes involved in carbohydrate and lipid metabolism 2011 [31] Celiac disease 20 21-week randomized double-blind Duodenal histologic Marsh score No significant differences in duodenal pathology was (Princess Alexandra placebo-controlled study Systemic IFN–g measured by found between hookworm infected and placebo injected xxx Hospital, Brisbane, 10 and 5 L3i NA or placebo SC at 0 and QE65–ELISpot groups Australia) 12 weeks. At week 20, subjects No significant difference in gluten-specific IFN-g- xxxx, underwent a 5 day 16 gram gluten producing PBMCs was observed following gluten challenge challenge between the study groups Vol.
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