Of Worms, Mice and Man

JPT-06663; No of Pages 15
Pharmacology & Therapeutics xxx (2014) xxxxxx
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Pharmacology & Therapeutics

journal homepage: www.elsevier.com/locate/pharmthera
Associate editor: P. Holzer
Of worms, mice and man: An overview of experimental and clinical helminth-based therapy for inammatory bowel disease
Marthe Heylen a,1, Nathalie E. Ruyssers a,1, Els M. Gielis a, Els Vanhomwegen a, Paul A. Pelckmans a,b, Tom G. Moreels a,b, Joris G. De Man a, Benedicte Y. De Winter a,
a b
Laboratory of Experimental Medicine and Pediatrics, Division of Gastroenterology, University of Antwerp, Antwerp, Belgium Antwerp University Hospital, Division of Gastroenterology & Hepatology, Antwerp, Belgium
a r t i c l e
i n f o
a b s t r a c t
The incidence of inammatory 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 inammatory bowel disease (IBD). The most likely mechanism for the suppression of immune responses by helminths is the release of helminthderived 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. 2014 Elsevier Inc. All rights reserved.
Keywords: Helminths Helminth-derived molecules Therapy Inammatory bowel disease Colitis Innate and adaptive immunity
Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2. Short overview of the immunological changes during IBD . . . . . . . . . 3. Animal models to mimic human intestinal inammation . . . . . . . . . 4. Helminths and helminth-derived molecules as therapeutic agents in IBD . . 5. What do we know about the underlying immunological mechanisms of 6. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conict of interest statement . . . . . . . . . . . . . . . . . . . . . . . . Acknowledgment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . protection? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 0 0 0 0 0 0 0 0 0
1. Introduction
Abbreviations: CDAI, Crohn's disease activity index; DC, dendritic cell; DNBS, dinitrobenzene sulfonic acid; DSS, dextran sulfate sodium; GMP, good manufacturing practice; IBD, inammatory bowel disease; IBDQ, inammatory bowel disease questionnaire; IFN-, interferon gamma; Ig, immunoglobulin; IL, interleukin; ILC, innate lymphoid cell; M2, alternatively activated macrophage; NK, natural killer; T cell, T lymphocyte; TGF-, transforming growth factor beta; Th, T helper lymphocyte; TNBS, trinitrobenzene sulfonic acid; TNF-, tumor necrosis factor alpha; Treg, regulatory T cell; UCDAI, ulcerative colitis disease activity index. Corresponding author at: Laboratory of Experimental Medicine and Pediatrics, University of Antwerp, Universiteitsplein, 12610 Antwerp, Belgium. Tel.: +32 3 265 27 10. E-mail address: benedicte.dewinter@uantwerpen.be (B.Y. De Winter). 1 Both authors have equally contributed.
Worldwide, about 4 to 5 million people suffer from Crohn's disease or ulcerative colitis, together known as inammatory bowel disease (IBD). IBD is a group of chronic inammatory disorders of the gastrointestinal tract, characterized by remitting and relapsing episodes of intestinal inammation, often resulting in symptoms such as intermittent abdominal pain, rectal bleeding, fever, weight loss, fatigue and diarrhea (Braus & Elliott, 2009). There is a broad arsenal of therapeutic options for IBD, including 5-aminosalicylates (e.g. sulfasalazine, mesalamine), corticosteroids (e.g. prednisone, budesonide), immunomodulators (e.g. azathioprine, methotrexate), antibiotics (e.g. cipro oxacin,
http://dx.doi.org/10.1016/j.pharmthera.2014.02.011 0163-7258/ 2014 Elsevier Inc. All rights reserved.
Please cite this article as: Heylen, M., et al., Of worms, mice and man: An overview of experimental and clinical helminth-based therapy for inammatory bowel disease, Pharmacology & Therapeutics (2014), http://dx.doi.org/10.1016/j.pharmthera.2014.02.011
M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx
metronidazole) and/or biologicals (e.g. in iximab, adalimumab) (Morrison et al., 2009; De Vroey & Colombel, 2011). However, no curative treatment is currently available (McSorley et al., 2013; Pedersen et al., 2014). The impact of IBD on the patient's quality of
life is high, as the onset of IBD typically occurs in the second and third decades of life, i.e. in the active socioeconomic years of one's life, and often leads to absenteeism (Xavier & Podolsky, 2007). The etiology of IBD still remains unknown, but a loss of immune tolerance to normal
commensal enteric ora in genetically susceptible individuals is postulated as the underlying pathogenic mechanism (Podolsky, 2002; Braus & Elliott, 2009; Scharl & Rogler, 2012). A rapid increase of IBD was seen during the second half of the twentieth century, especially in the industrialized, developed Western countries (Lapidus, 2001). Industrialization was accompanied by improved hygiene, sanitation and medical conditions and regulated food industries which have led to the eradication of infectious agents such as parasitic worms (helminths) (Feillet & Bach, 2004; Elliott et al., 2007). For example, the prevalence of hookworm infections, an intestinal nematode, in North American schoolchildren dropped from 65% in the 1910s to less than 2% in the 1980s (Elliott & Weinstock, 2012a). It is suggested that the lack of exposure to helminths contributes to the susceptibility for immune-related diseases such as IBD (Elliott et al., 2000), asthma, atopic eczema, allergic rhinoconjunctivitis (van den Biggelaar et al., 2000; Cooper et al., 2003; Rautava et al., 2004; van den Biggelaar et al., 2004; Yazdanbakhsh & Wahyuni, 2005; Wordemann et al., 2008), multiple sclerosis (Fleming, 2013), cardiovascular diseases (Magen et al., 2005), rheumatoid arthritis (Harnett & Harnett, 2009) and type 1 diabetes mellitus (Cooke et al., 2004; Zaccone et al., 2009). Epidemiological, experimental and clinical data now support the idea that helminths provide protection against immune-mediated diseases. However, the mechanism by which helminths provide this protection is not yet fully understood. It is known that helminths release helminth-derived immunomodulatory molecules which may be responsible for the suppression of immune responses (Ruyssers et al., 2008). 2. Short overview of the immunological changes during IBD The clinical manifestations of IBD result from complex interactions between genetic factors, environmental factors and the immune system (Fiocchi, 1998, 2012; Speight & Manseld, 2013). Under normal circumstances, mucosal immune responses are tightly regulated to ensure gut homeostasis. The mucosal immune system balances between a protective response to pathogenic antigens and tolerance to antigens from food and common bacterial luminal ora (Neuman, 2007). However, it is postulated that in IBD this important immunological homeostasis is disrupted leading to uncontrolled chronic inammation towards intraluminal antigens of bacterial origin (Plevy, 2002; Bamias et al., 2005; Jeon et al., 2013). The precise role of bacteria in the etiology of IBD remains elusive but three theories, not necessarily mutually exclusive, have been proposed: (1) an unidentied persistent pathogen, (2) an abnormally permeable mucosal barrier leading to excessive bacterial translocation and (3) a breakdown in the balance of the gut microbiome called dysbiosis (De Hertogh et al., 2008; Shim, 2013). Published data suggest that mucosal and fecal microora differ between IBD patients and healthy controls (De Hertogh et al., 2008; Knights et al., 2013). Evidence exists in favor of an intestinal barrier dysfunction in IBD providing access of luminal antigens to the underlying tissue (Baumgart & Carding, 2007; Pastorelli et al., 2013). The perturbations in the luminal barrier function in IBD include a reduction of secretions, a reduced number of secretory cells and disabled tight junctions (McGuckin et al.,
2009). Increased permeability of both the inamed and non-inamed mucosa has been described in IBD patients (Soderholm et al., 2002). Antigens breaking through this disturbed barrier are subsequently phagocytosed by antigen presenting cells such as dendritic cells (DCs) and macrophages. DCs and macrophages are key cells in controlling immune responses presenting antigenic peptides via the major histocompatibility complex class II molecules to lymphocytes (Cader & Kaser, 2013). It is assumed that DCs and macrophages in healthy individuals stimulate naive T cells to differentiate into regulatory T (Treg) cells which play an important role in controlling immune homeostasis and maintaining tolerance (Fig. 1A). On the contrary, activated DCs and macrophages in IBD patients stimulate T cells to differentiate into proinammatory T helper (Th) 1 and Th17 effector cells (Fig. 1B) (Baumgart & Carding, 2007; Rutella & Locatelli, 2011). Patients suffering from IBD have disturbed clearance of these proinammatory Th1 and Th17 cells which might overwhelm regulatory control mechanisms and can result in inammation. On the other hand, IBD may develop due to a failure of Treg cells and their corresponding regulatory cytokines, such as interleukin (IL)-10 and tissue growth factor (TGF)-, to control inammation and effector pathways (Eksteen et al., 2005; Baumgart & Sandborn, 2012). Proinammatory cytokines such as IL-2, IL-12 and interferon (IFN)- produced by activated Th1 cells stimulate macrophages to secrete large amounts of other proinammatory cytokines e.g. tumor necrosis factor (TNF)-, IL-1 and IL-6 (Moreels & Pelckmans, 2005; Neuman, 2007). These cytokines amplify the proinammatory immune response by promoting the proliferation of effector Th1 and Th17 cells and by stimulating the release of chemokines which will attract more inammatory cells to the site of inammation (Baumgart & Carding, 2007; Neuman, 2007). Overall, a disruption of the immune balance whereby proinammatory Th1 and Th17 cells and their corresponding proinammatory cytokines outnumber the regulatory T cell responses can lead to inammation (Fig. 2A). Finding ways to inuence the immunological process during inammation might contribute to the development of new therapeutic options in IBD. 3. Animal models to mimic human intestinal inammation Helminths and helminth-derived molecules provide a promising new therapy against IBD. The underlying mechanisms of how these organisms inuence the immune system to attenuate inammation are a topic of increasing research interest. Animal models of intestinal inammation provide powerful tools for the investigation of the pathogenesis of IBD (Wirtz & Neurath, 2007). Although these models do not exactly represent the complexity of human disease, they have similar immunological and histopathological features (Elson et al., 2005; Mizoguchi & Mizoguchi, 2008). In addition to the study of the pathogenesis, animal models also allow the testing of new therapeutic strategies in the preclinical phase (Wirtz & Neurath, 2000, 2007). Several experimental animal models are available to investigate intestinal inammation. They can be divided into four different categories: spontaneous models, inducible models, genetically engineered models (transgenic mice, knockout mice) and adoptive
Fig. 1. Immunology of the mucosa of the small intestine in a healthy (A) and inammatory condition (B). Within the Peyer's patch matrix lies a mix of immune cells from both the innate immune system (e.g. DCs and macrophages) and the adaptive immune system (e.g. T and B lymphocytes), which forms a barrier against microbial invasion. An important function of the Peyer's patch is antigen sampling, as Peyer's patches have a thin mucus layer and contain specialized phagocytic cells called M cells, which can transport material across the epithelial barrier. DCs and macrophages present in the matrix of the Peyer's patch sample antigens that are then broken down. These antigen-loaded DCs and macrophages present the antigens to Th0 cells in the T cell zone of the Peyer's patch or mesenteric lymph nodes. In healthy conditions (A), the Th0 cells differentiate into immune modulatory Treg cells. The activation of Treg cells results in an anti-inammatory response, as Treg cells migrate back to the lamina propria of the villi via the efferent lymphatic vessels and the bloodstream, and secrete molecules such as IL-10 and TGF-, which exert a suppressive action on the immune cells within the lamina propria. IL-10 and TGF- are therefore critical in maintaining immune tolerance and preventing unnecessary inammation. Defects in the function of Treg cells are associated with IBD (B). It is assumed that barrier disruption, due to enteric bacterial triggers and genetic susceptibility, can lead to intestinal inammation. In this case, epithelial cells which are in contact with commensal enteric bacteria are activated leading to bacterial inux in the Peyers' patches. DCs and macrophages consider these bacteria as foreign and are activated and converted into inammatory DCs or M1 macrophages. These DCs and M1s start to release inammatory molecules such as IL-1, IL-6, IL-12, IL-18, IL-23 and IL-27. Due to this inammatory environment, proinammatory effector T cells such as Th1 and Th17 cells are differentiated from Th0 cells. The Th1 and Th17 cells migrate via the efferent lymphatic vessels and the bloodstream back to the lamina propria where they coordinate an escalation of the immune response by secreting their own inammatory molecules such as IFN-, IL-2 and IL-17 which can lead to intestinal inammation. B: B lymphocyte; DC: dendritic cell; IEL: intraepithelial lymphocyte; IFN-: interferon-; IL: interleukin; ILC: innate lymphoid cell; M1: classically activated macrophage; M cell: microfold cell; TGF-: transforming growth factor-; Th0: naive T lymphocyte; Th1: T helper 1 lymphocyte; Th17: T helper 17 lymphocyte; Treg: regulatory T lymphocyte.
Fig. 2. Immune proles during Crohn's disease (A) and the hypothesized immune prole of helminth-based therapy in Crohn's disease (B). The immune balance in Crohn's disease patients is disrupted (A), as it is primarily driven by Th1 and Th17 cells, M1 and DCs and their corresponding proinammatory cytokines such as TNF-, IFN-, IL-17, IL-1, IL-2, IL-6, IL-12 and IL-23. This proinammatory response outnumbers the Treg cell response, responsible for controlling immunity and maintaining tolerance. Therefore the immune balance shifts towards the proinammatory side resulting in inammation. Thanks to the immune regulatory mechanisms of helminths, it is hypothesized that helminth-based therapy in Crohn's disease patients (B) can restore the immune balance by creating a regulated environment in which the proinammatory Th1 and Th17 responses are suppressed. To obtain that goal, Treg activity needs to be restored and Th2, M2 macrophages and tolerogenic DC responses are induced with an increase in corresponding regulatory cytokines such as IL-10 and TGF-, IL-4, IL-5 and IL-13. DC: dendritic cell; IFN-: interferon-; IL: interleukin; M1: classically activated macrophage; M2: alternatively activated macrophage; TGF-: transforming growth factor-; Th1: T helper 1 lymphocyte; Th2: T helper 2 lymphocyte; Th17: T helper 17 lymphocyte; TNF-: tumor necrosis factor-; tolDC: tolerogenic DC; Treg: regulatory T lymphocyte.
transfer models (Wirtz & Neurath, 2000, 2007; Dothel et al., 2013). Models of spontaneous colitis include C3H/HeJBir mice, SAMP1/Yit mice and the cotton-top tamarin model (Wirtz & Neurath, 2000; Jurjus et al., 2004). Experimental inammation of the gut can also be induced by various mechanical or chemical methods leading to disruption of the mucosal barrier. Examples of inducible colitis models are acetic-acid colitis, dextran sulfate sodium (DSS) colitis and dinitrobenzene and trinitrobenzene sulfonic acid (DNBS and TNBS) colitis (Wirtz & Neurath, 2000; Kawada et al., 2007; Wirtz et al., 2007). The use of genetically engineered models allows the study of immunoregulatory pathways and they include the IL-2 and IL-10 knockout (IL-2/ and IL-10/) mice and the IL-7 and signal transducer and activating transcription (STAT) 4 transgenic mice (Wirtz & Neurath, 2000, 2007). The pioneering work of Powrie et al. led to the adoptive transfer models where inammation is induced by the selective transfer of certain immune cell types (e.g. IL-10 / T cells, CD4+CD25CD62L+ T cells, CD45RBhiCD4+ T cells) to immunocompromised host animals (Powrie et al., 1993; Read & Powrie, 2001, chap. 15; Ostanin et al., 2006). The models most widely used for the study of helminthic therapy during intestinal inammation are the DSS, DNBS and TNBS model, and the T cell transfer colitis model (Elliott & Weinstock, 2012b). 4. Helminths and helminth-derived molecules as therapeutic agents in IBD 4.1. Why helminths can be used to ameliorate gut inammation Helminths have always colonized humans and consequently have co-evolved with their hosts (Dunne & Cooke, 2005). It is thought that helminths were free-living organisms that adapted to parasitic life cycles to ensure their survival when environmental conditions were poor (Mulcahy et al., 2004). Many of the various helminth species have different life cycles and occupy different niches in their hosts, e.g. the intestinal lumen, blood stream or lymphatics (Weinstock et al., 2005). Although different helminth species may evoke somewhat different host immune responses due to different life cycles, there are many similarities in these reactions (Meeusen, 1999; Jackson et al.,
2009). During helminth infection the host evokes a strong Th2 immune response that involves IL-4, IL-5, IL-9, IL-10 and IL-13 cytokine release, the production of immunoglobulins (Ig) IgG1, IgG4 and IgE and the activation of dendritic cells, eosinophils, basophils, mast cells and alternatively activated macrophages (M2) to provide protection against worm colonization (Fig. 3) (Maizels et al., 2004; Allen & Maizels, 2011; Salgame et al., 2013). To ensure survival within their host, helminths developed immune mechanisms to prevent evasion such as migratory strategies together with the induction of Treg cells and the production of their regulatory cytokines IL-10 and TGF- which leads to a more immunosuppressive state in the host (Fig. 3) (Elliott et al., 2005; Maizels et al., 2012; Taylor et al., 2012). More recently attention is being paid to the innate immune cells. As part of the innate immune system, phagocytes like monocytes, macrophages and DCs, and cytotoxic cells like natural killer cells will respond to pathogen associated molecular patterns (Medzhitov & Janeway, 2000; Pulendran & Artis, 2012). These cells will be the rst responders towards helminths and their products and they will subsequently skew the adaptive immune response towards Th2 and Treg responses which is suggested to suppress the damaging Th1 and Th17 effector cells, responsible for maintaining the inammation in IBD (Ruyssers et al., 2008; McSorley & Loukas, 2010; Khan & Fallon, 2013) (Fig. 2B). 4.2. Helminthic therapy: animal studies A vast amount of experimental data supports the hypothesis that helminths are able to modulate IBD. The possible benecial effects of helminth infections on the development and the course of colitis have been investigated in different animal models (Weinstock & Elliott, 2013). Preliminary data of Elliott et al. (2000) rst conrmed that the loss of exposure to helminths increased the risk of intestinal inammation when they found that mice pre-exposed to Schistosoma mansoni were protected from developing TNBS-induced colitis and that IL-10/ mice treated with Heligmosomoides polygyrus bakeri third stage larvae developed signicantly less intestinal inammation. Furthermore, this group showed that Trichuris muris eggs signicantly attenuated intestinal inammation in IL-10/ mice and protected mice from
driven colitis (Setiawan et al., 2007; Sutton et al., 2008; DonskowLysoniewska et al., 2012; Leung et al., 2012). However, H. polygyrus bakeri larvae enhanced Citrobacter rodentium-induced infectious colitis in mice (Chen et al., 2005, 2006) and failed to prevent colitis in TGFRII DN mice (i.e. mice with interrupted T cell TGF- signaling), suggesting the requirement of TGF- signaling through mucosal T cells for the control of colitis (Ince et al., 2009). Infection with H. diminuta larvae in DNBS mice had a profound anti-colitis effect (both prophylactically and as a treatment), which was not seen in semipermissive rats (Hunter et al., 2005, 2010; Melon et al., 2010). In contrast, H. diminuta infection caused an exacerbation of oxazolone-induced colitis in mice (Hunter et al., 2007; Wang et al., 2010). T. muris-infected IL-10/ mice were not protected from developing a severe colitis (Wilson et al., 2011). Worthwhile mentioning is also the study of Broadhurst et al. (2012) who used macaque monkeys with idiopathic chronic diarrhea, a preclinical model for ulcerative colitis. Treatment of these nonhuman primates with Trichuris trichiura eggs resulted in clinical improvement in fecal consistency and weight gain. As shown in Table 1, most of these studies clearly indicate that several species of helminths exert both prophylactic and therapeutic efciency in different models of experimental colitis in animals, although the studies also indicate that helminthic therapy is both disease- and helminth-specic (McKay & Wallace, 2009). 4.3. Helminthic therapy: clinical studies
Fig. 3. Immune proles during helminth infection. During helminth infection, helminths attach to or traverse through the epithelial cell layer. Damaged epithelial cells release alarmins such as IL-25, IL-33 and TSLP. These alarmins together with helminth-derived products promote a Th2 and Treg response through the tolerogenic activation of DCs. The evoked Th2 response results in IL-4, IL-5, IL-13, IL-9, IL-10 cytokine release and the production of immunoglobulins IgG1, IgG4 and IgE which on their turn drive the activation of M2 macrophages, mast cells, eosinophils and basophils. B: B lymphocyte; DC: dendritic cell; Ig: immunoglobulin; IL: interleukin; M2: alternatively activated macrophage; TGF-: transforming growth factor-; Th2: T helper 2 lymphocyte; tolDC: tolerogenic DC; Treg: regulatory T lymphocyte; TSLP: thymic stromal lymphopoietin.
TNBS colitis (Elliott et al., 2000). These preliminary data have led to a rst complete report on the benecial effect of helminths on the course of DSS-induced colitis (Reardon et al., 2001). They were able to show that Hymenolepis diminuta infection, either prophylactic or therapeutic, caused a signicant amelioration of DSS associated ion transport abnormalities in the colon. However, no improvements in colonic histopathology were observed (Reardon et al., 2001). Since then, several studies showed that helminth infections of different species have benecial preventive and therapeutic effects on experimental colitis, although the underlying mechanisms to reach the positive effects may differ between different helminth species. What follows is an overview of all the experimental studies conducted so far. Table 1 summarizes the studies explicating the helminths tested, the animal models used, the outcomes measured and the suggested mechanisms of action. We and others demonstrated that an infection with S. mansoni cercariae exerted preventive effects on the course of TNBS-induced colitis in rats and DSS-induced colitis in mice (Moreels et al., 2004; Smith et al., 2007; Bodammer et al., 2011). Furthermore, S. mansoni eggs prevented mice from developing TNBS-induced colitis, but did not prevent mice from developing DSS colitis (Elliott et al., 2003; Smith et al., 2007). Schistosoma japonicum eggs also exerted preventive effects on TNBS-induced colitis in mice (Zhao et al., 2009; Xia et al., 2011). A prior infection of mice with Trichinella spiralis larvae and Trichinella papuae larvae reduced the severity of DNBS- and DSS-induced colitis respectively (Khan et al., 2002; Adisakwattana et al., 2013). H. polygyrus bakeri larvae had different effects on different animal models of colitis. For example, they suppressed established colitis in piroxicam treated IL-10/ mice (Elliott et al., 2004, 2008), they exerted both preventive and therapeutic effects on colitis in the IL10/ T cell transfer model in mice (Metwali et al., 2006; Hang et al., 2010; Blum et al., 2012) and they protected mice from TNBS-induced, DSS-induced and antigen-
Soon after the rst promising ndings of helminth infections on experimental colitis were published, clinical trials were started to explore whether helminths could alter the course of disease in IBD patients. These studies are summarized in Table 2 describing the study protocol, parameters measured and main outcomes. Summers et al. (2003, 2005a,b,c) were the rst to conduct three small clinical trials, in which patients with ulcerative colitis or Crohn's disease consumed viable embryonated eggs (ova) of the pig whipworm Trichuris suis. In the rst small open-label trial, a single dose of 2500 T. suis ova was tested in 4 Crohn's disease and 3 ulcerative colitis patients and patients were followed every 2 weeks for 12 weeks. Furthermore, repeated doses of 2500 T. suis ova, at 3-week intervals for 28 weeks, were tested in 2 Crohn's disease and 2 ulcerative colitis patients. During both treatment regimens, all patients had improvement in their symptoms without side effects. After a single dose of T. suis ova, 3 of the 4 patients with Crohn's disease achieved remission according to the Crohn's Disease Activity Index (CDAI b= 150) and all ulcerative colitis patients achieved remission according to the Simple Clinical Colitis Activity Index (SCCAI b= 4). Although this benecial effect was temporary, it was shown that repeated doses of T. suis ova sustained clinical improvement in all patients (Summers et al., 2003). In the second small openlabel trial including 29 active Crohn's disease patients, 79.3% of the patients responded to repeated doses of 2500 T. suis ova given every 3 weeks for 24 weeks (decrease in CDAI N 100 points), while 72.4% of the patients achieved remission (CDAI b= 150) (Summers et al., 2005a). The third trial was a randomized double-blind placebocontrolled trial including 54 active ulcerative colitis patients. It revealed that a signicant number of ulcerative colitis patients (43.3%) receiving repeated doses of 2500 T. suis ova every 2 weeks for 12 weeks responded (Ulcerative Colitis Disease Activity Index (UCDAI) b 4) compared to placebo-treated ulcerative colitis patients (16.7%). However, no signicant differences in remission rates were observed between both treatment groups (UCDAI b 2) (Summers et al., 2005b). After these promising results, the United States Food and Drug Administration requested the development of T. suis ova under good manufacturing practice (GMP) and appropriate safety testing in order to continue clinical tests. Consequently, a small randomized doubleblind placebo-controlled trial was initiated, testing the tolerability and safety of different doses of GMP-approved T. suis ova (http:// clinicaltrials.gov/ trial identier NCT01434693) (Sandborn et al.,
6 Table 1
Effects of helminths on colitis in experimental animal studies. Authors & year Reardon et al., 2001 Helminth Hymenolepis diminuta larvae Class Cestode Host Mouse Colitis model DSS colitis Outcome Mechanisms of action
Assumed Th2 response Preventive and curative treatment: normalization of colonic ion transport, but no improvement in colonic histopathology Preventive treatment: attenuation of colitis Preventive treatment: attenuation of colitis Preventive treatment: attenuation of colitis Curative treatment: suppression of established colitis Preventive treatment: attenuation of colitis Curative treatment: enhanced recovery of colitis Augmented Th2 response (IL-4, IL-13) Diminished Th1 response (IFN-), augmented Th2 response (IL-4), Treg response (IL-10 mRNA expression), STAT6-mediated response required for protection Augmented Th2 response (IL-4) Diminished Th1 response (IL-12, IFN-), augmented Th2 response (IL-13), Treg response (Foxp3 mRNA expression) Augmented Th2 response (IL-4, IL-10 mRNA expression), IL-10 required for protective effect Not specied Augmented Th2 response (IL-4, IL-5, IL-10), augmented Treg response (IL-10), changes in Th1 response (IFN-, TNF-), STAT6-mediated mechanism CD11c+ DC expansion and IL-10 mRNA expression
Khan et al., 2002 Elliott et al., 2003
Trichinella spiralis larvae Schistosoma mansoni eggs Schistosoma mansoni larvae
Nematode
Mouse
DNBS colitis TNBS colitis
Trematode Mouse
Moreels et al., 2004 Elliott et al., 2004
Trematode Rat Mouse
TNBS colitis IL-10/ colitis DNBS colitis
Heligmosomoides Nematode polygyrus bakeri larvae Hymenolepis diminuta larvae Cestode
Hunter et al., 2005
Mouse
Hunter et al., 2005 Chen et al., 2005
Hymenolepis diminuta larvae
Cestode
Rat Mouse
DNBS colitis Citrobacter rodentiuminduced colitis Citrobacter rodentiuminduced colitis IL10/ T cell transfer colitis Oxazolone colitis DSS colitis DSS colitis TNBS colitis
Preventive treatment: no effect on colitis Preventive treatment: worsening of Citrobacter rodentium-induced infectious Colitis preventive treatment: worsening of Citrobacter rodentiuminduced infectious colitis Curative treatment: reversal of established colitis Preventive treatment: worsening of colitis Preventive treatment: protection from colitis Preventive treatment: worsening of colitis Preventive treatment: protection from colitis Curative treatment: improvement of established colitis Preventive treatment: attenuation of colitis Preventive treatment: attenuation of colitis
Heligmosomoides Nematode polygyrus bakeri larvae Heligmosomoides Nematode polygyrus bakeri larvae Heligmosomoides Nematode polygyrus bakeri larvae Hymenolepis diminuta larvae Schistosoma mansoni larvae Schistosoma mansoni eggs Cestode
Chen et al., 2006
Mouse
Metwali et al., 2006
Mouse
Appearance of CD8+ regulatory T cells
Hunter et al., 2007 Smith et al., 2007 Smith et al., 2007 Setiawan et al., 2007 Elliott et al., 2008
Mouse
Augmented Th2 response (IL-4, IL-5, IL-13, IL-10), changes in Treg response Induction of F4/80+CD11b+CD11c macrophages Not specied Diminished Th1 response (IL-12p40, IFN-), augmented Treg response (IL-10) IL-4 and IL-10 mediated inhibition of Th17 response (IL-17)
Trematode Mouse Trematode Mouse Mouse
Heligmosomoides Nematode polygyrus bakerilarvae Heligmosomoides Nematode polygyrus bakeri larvae Heligmosomoides Nematode polygyrus bakeri larvae Schistosoma japonicum eggs Nematode
Mouse
IL-10/ colitis TNBS colitis
Sutton et al., 2008
Mouse
Diminished Th1 response (TNF-, IFN- mRNA expression), augmented Th2 response (IL-4, IL-13 mRNA expression), mast cell-mediated effect Changes in Th1 response (IFN-, =TNF-), augmented Th2 response (IL-10 mRNA expression), downregulation of TLR4 mRNA expression related to IFN- and IL-10 IL-10 secretion requires intact T cell TGF- signaling
Zhao et al., 2009
Mouse
TNBS colitis
Ince et al., 2009
Heligmosomoides Nematode polygyrus bakeri larvae Heligmosomoides Nematode polygyrus bakeri larvae Hymenolepis diminuta larvae Hymenolepis diminuta larvae Cestode Cestode
Mouse
TGF-RII DN Preventive treatment: no effect on colitis colitis IL10/ T cell transfer colitis Oxazolone colitis DNBS colitis Preventive and curative treatment: suppression of colitis Preventive treatment: worsening of colitis Preventive treatment: protection from colitis
Hang et al., 2010
Mouse
Alteration of intestinal DC function resulting in diminished IFN- and IL-17 responses Involvement of Th2 response (IL-5 and recruitment of eosinophils) Diminished Th1 response (TNF-, IFN-), augmented Th2 response (IL-4, IL-10, eosinophils), augmented Treg response (IL-10)
Wang et al., 2010 Melon et al., 2010
Mouse Mouse
M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx Table 1 (continued) Authors & year Hunter et al., 2010 Bodammer et al., 2011 Xia et al., 2011 Helminth Hymenolepis diminuta larvae Schistosoma mansoni larvae Schistosoma japonicum eggs Trichuris muris eggs Class Cestode Host Mouse Colitis model DNBS colitis DSS colitis TNBS colitis Outcome Preventive treatment: attenuation of colitis Preventive treatment: attenuation of colitis Preventive treatment: attenuation of colitis Exacerbation of colitis Mechanisms of action Mobilization of alternatively activated macrophages Diminished Th1 response (TNF-, IL-2 mRNA expression), diminished Th2 response (IL-4 mRNA expression) Diminished Th1 response (TNF-, IFN-), maintaining epithelial barrier function trough augmented tight junction proteins Augmented Th1 response (IFN-), augmented Th17 response (IL-17A), IL-13 decoy receptor (IL-13R2) resulting in IL-13 activity Induction of tolerogenic DCs
Trematode Mouse Nematode Mouse
Wilson et al., 2011
Nematode
Mouse
L-10/ colitis IL10/ T cell transfer colitis DSS colitis
Blum et al., 2012
Heligmosomoides Nematode polygyrus bakeri larvae Heligmosomoides Nematode polygyrus bakeri larvae Heligmosomoides Nematode polygyrus bakeri larvae Trichuris trichiura eggs Nematode
Mouse
Preventive treatment: protection from colitis Curative treatment: protection from colitis Preventive treatment: protection from colitis Curative treatment: clinical improvement in fecal consistency and weight gain
DonskowLysoniewska et al., 2012 Leung et al., 2012
Mouse
Augmented macrophage inltration (IL-1, TNF-, IL-6), augmented expression of MOR1, POMC and -endorphin Diminished Th1 response (IFN-), diminished Th17 response (IL-17), induction of Foxp3+ Treg cells, IL-10 from non-T cells Augmented Th2 response (CD4+ T cells producing IL-4), diminished fraction of Ki67+ CD4+ T cells (which are indicators of ongoing inammation), diminished Th1-type inammatory gene expression, augmented gene expression associated with IgE signaling, mast cell, eosinophil and alternatively activated macrophage activation, reduced bacterial attachment to the intestinal mucosa and changes in composition of attached bacteria Changes in Treg response
Mouse
Antigendriven colitis
Broadhurst et al., 2012
Macaques Idiopathic monkeys chronic diarrhea
Adisakwattana et al., 2013
Trichinella papuae larvae
Nematode
Mouse
DSS colitis
Preventive treatment: attenuation of colitis
CD: cluster of differentiation; DCs: dendritic cells; DNBS: dinitrobenzene sulfonic acid; DSS: dextran sulfate sodium; Foxp3: forkhead box p3; IFN-: interferon-; IgE: immunoglobulin E; IL: interleukin; IL10/: IL-10 decient; MOR1: -opioid receptor; POMC: proopiomelanocortin; STAT6: signal transducer and activator of transcription 6; TGF-: transforming growth factor-; TGF-RII DN: interrupted T cell TGF- signaling; Th: T helper cells; TLR4: toll-like receptor 4; TNBS: trinitrobenzene sulfonic acid; TNF-: tumor necrosis factor-; Treg: regulatory T cells.
2013). Crohn's disease patients receiving a single dose of 500, 2500, 7500 GMP-approved ova or placebo did not show short-term (2 weeks) or long-term (6 months) treatment-related adverse effects, and a single dose of T. suis ova up to 7500 was well tolerated (Sandborn et al., 2013). In the meantime, a small open-label trial with the human hookworm Necator americanus was conducted in Crohn's disease patients (Croese et al., 2006). Twenty weeks postinfection, the average CDAI and the average Inammatory Bowel Disease Questionnaire (IBDQ) improved (CDAI b= 150 and IBDQ N= 170). However, 2 out of 9 patients with moderately active disease showed a worsening in symptom scores after they received 50 infective larvae (L3i) (Croese et al., 2006). Recently, two multicenter randomized double-blind placebo-controlled Phase II trials were conducted in the USA (TRUST-I: trial identier NCT01576471 (Coronado Biosciences)) and in Europe (TRUST-II: trial identier NCT01279577 (Dr. Falk Pharma)), testing the safety and efcacy of a 12 week treatment with GMP-approved T. suis ova in patients with moderate to severe Crohn's disease. In a recent press release Coronado Biosciences announced the results of the TRUST-I trial. Although the primary endpoint of the study was not met (there was no difference between the response rate of patients on T. suis ova versus placebo), they postulate that there was a non-signicant improved response after treatment with T. suis ova in patients with more severe Crohn's disease (CDAI N 290) (Coronado Biosciences Press Release, 2013). The results of the TRUST-II study are expected by the end of March 2014. In two additional trials, the safety and effectiveness of T. suis ova in ulcerative colitis patients will be tested and the changes in the mucosal immune response will be evaluated (trial identier NCT01953354 and NCT01433471). Both studies are still recruiting participants. Helminthic therapies are not only being tested in IBD patients, but also in patients with other inammatory
diseases. Helminthic therapy in multiple sclerosis showed a trend towards reduced numbers of new lesions (Correale & Farez, 2007; Correale et al., 2008; Correale & Farez, 2011; Fleming, 2011; Fleming et al., 2011; Benzel et al., 2012) whereas no changes in clinical symptoms are observed in allergic rhinitis, allergic rhinoconjunctivitis and asthma (Blount et al., 2009; Bager et al., 2010; Feary et al., 2010; Bager et al., 2011). Helminthic therapy in celiac disease showed a suppression of intestinal inammatory cytokines without a clinical benet (Daveson et al., 2011; McSorley et al., 2011). A clinical trial studying the effect of T. suis ova for allergies to peanuts and tree nuts (trial identier NCT01070498) has been completed, but no data are available yet. Clinical trials to test the effect of T. suis ova in autism spectrum disorders (trial identier NCT01040221) and chronic plaque psoriasis (trial identier NCT01948271) will soon be launched. In addition, helminthic therapy is also under consideration in transplantation (Johnston et al., 2014). A new emerging phenomenon is patients self-treating with helminths. Some IBD patients do not do well on conventional therapy and seek their own alternative solutions, rather than waiting for the time-consuming approval processes of new therapies (Weinstock, 2012). For example, there are reports documenting that Crohn's disease patients buy helminths on the internet, infect themselves and share their clinical experience through online forums with other patients (Broadhurst et al., 2010; Flowers & Hopkins, 2013). 4.4. Helminth-derived molecules as therapeutic agents As described above, T. suis was shown to be a safe therapeutic approach showing no short- or long-term treatment related adverse effects. This agent has received GMP approval and is now licensed to
the pharmaceutical industry. Although helminth infections have proven to be effective against IBD, introducing living helminthic therapy into the clinic may still encounter some problems. For example, patients might nd it hard to accept being infected with a living helminth, leading to poor treatment adherence (Ruyssers et al., 2008). It also remains to be seen whether large scale production of living helminths (e.g. larvae or embryonated eggs) under GMP can satisfy the demand from large numbers of patients (McSorley et al., 2013). Furthermore, little is known about the variation in human responses to helminths: persistent infection and/or invasion of the helminth in other tissues in the human host cannot be excluded and might cause pathology (Ruyssers et al., 2008; McSorley et al., 2013). Garg et al. (2014) recently showed that there is currently not enough data available to draw conclusions regarding the efcacy and safety of helminthic therapy to treat patients with IBD. As long as the risk/benet ratio in patients is not fully understood, caution is advised when using living helminths
(Levison et al., 2010; Hernandez et al., 2013). Therefore, the identication, the characterization and the synthetic engineering of helminthderived immunomodulatory molecules responsible for the antiinammatory effect might overcome these possible drawbacks and might lead to new therapeutic approaches in IBD without the need for living helminth infection. Several experimental animal studies with helminth-derived immunomodulatory molecules, with or without benecial effects on colitis, have already been published and are summarized in Table 3. Attenuation or suppression of DSS-induced colitis in mice was demonstrated by recombinant Acanthocheilonema viteae cystatin, a secreted cysteine protease inhibitor, recombinant Toxascaris leonine galectin-9 homologue (rTl-GAL), recombinant Anisakis simplex macrophage migration inhibitory factor-like protein (rAs-MIF), recombinant type I cystatin of Clonorchis sinensis (rCsSten-1) and Ancylostoma ceylanicum excretory/ secretory products (AcES) and adult worm crude extracts ( AcAw)
Table 2 Clinical studies of helminthic therapy in Crohn's disease and ulcerative colitis patients. Authors & year Summers et al., 2003 Study protocol and number of subjects Single dose testing of 2500 T. suis ova p.o., monitoring patients every 2 wk for N= 12 wk and repeated dose testing of 2500 T. suis ova p.o. at 3-wk intervals, monitoring patients every 3 wk for 28 wk: 4 CD patients of which 2 given repeated doses 3 UC patients of which 2 given repeated doses Clinical evaluation parameters Safety: clinical and laboratory tests Efcacy (remission): IBDQ N= 170 points CDAI b= 150 points SCCAI b= 4 points Main effects No adverse effects Single dose testing: 75% CD patients achieved remission, 67% relapsed within 12 wk 100% UC patients achieved remission, 33% relapsed within 12 wk Repeated dose testing: 100% CD and UC patients achieved remission, 50% CD patients and 100% UC patients remained in remission for N= 1 yr No adverse effects Repeated dose testing: 75.9% CD patients responded within 12 wk 79.3% CD patients responded within 24 wk 65.5% CD patients remitted within 12 wk 72.4% CD patients remitted within 24 wk No adverse effects Repeated dose testing: 43.3% UC patients treated with T. suis ova vs. 16.7% UC patients treated with placebo responded within 12 wk (p = 0.04) 10% UC patients treated with T. suis ova vs. 4.2% UC patients treated with placebo remitted (not signicant) within 12 wk Adverse effects: mild itch, painful transient enteropathy, eosinophilia CDAI improved 20 weeks and 45 weeks postinfection compared to baseline Mean 165 (wk 1) vs. 64 (wk 20) (p = 0.132) Mean 165 (wk 1) vs. 75 (wk 45) (p = 0.246) IBDQ improved 20 weeks postinfection: Mean 151 (wk 14) vs 179 (wk 20) Each T. suis ova dose was well tolerated 25.9% of T. suis ova-treated CD patients vs. 33.3% placebo-treated CD patients reported gastrointestinal disturbances No dose-dependent relationship for adverse effects was observed: 33.3% placebo-treated patients, 44.4% 500 T. suis ova-treated patients, 0% 2500 T. suis ovatreated patients and 33.3% 7500 T. suis ova-treated patients experienced at least 1 gastrointestinal event
Summers et al., 2005a
Repeated dose testing of 2500 T. suis ova p.o. at 3-wk intervals for 24 wk: 29 active CD patients
Safety: patient diaries for adverse effects Efcacy (response): decrease in CDAI N 100 points Efcacy (remission): CDAI b= 150 points
Summers et al., 2005b
Repeated dose testing of 2500 T. suis ova or placebo p.o. at 2-wk intervals for 12 wk: 54 active UC patients
Safety: patient diaries for adverse effects Efcacy (response): UCDAI b 4 points Efcacy (remission): UCDAI b 2 points
Croese et al., 2006
Efcacy (remission): Single dose testing of 2550 N. americanus CDAI b= 150 points IBDQ N= 170 points infective larvae (L3i) s.c. at wk 0 and repeated dose testing of 2550 N. americanus infective larvae (L3i) s.c. at wk 0 and wk 27 or 30: 9 CD patients of which 5 given repeated doses
Sandborn et al., 2013
Single dose testing of 3 different doses (500, 2500 or 7500) GMP-approved T. suis ova or placebo p.o., monitoring patients 1, 3, 5, 7, 9, 11 and 14 days postinfection and 1, 2 and 6 months postinfection: 36 CD patients 3 cohorts of 12 patients (9 treated with 500, 2500 or 7500 T. suis ova and 3 treated with placebo)
Safety and tolerability: Telephone calls and patients diaries to follow-up adverse effects, changes to concomitant medications and gastrointestinal signs and symptoms Physical examination, assessment of adverse effects and review of reported gastrointestinal signs and symptoms at day 14 postinfection Stool sample at month 6 postinfection
CD: Crohn's disease; CDAI: Crohn Disease Activity Index; GMP: Good Manufacturing Practice; IBDQ: Inammatory Bowel Disease Questionnaire; N. americanus: Necator americanus; p.o.: per os; SCCAI: Simple Clinical Colitis Activity Index; s.c.: subcutaneous; T. suis: Trichuris suis; UC: ulcerative colitis; UCDAI: Ulcerative Colitis Disease Activity Index; wk: week.
M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx Table 3 Effects of helminth-derived molecules on colitis in experimental animal studies. Authors & year Schnoeller et al., 2008 Helminth-derived molecule Acanthocheilonema viteae cystatin (recombinant) Class Nematode Host Colitis model Outcome Preventive treatment: reduction of the epithelial damage and inammatory cell inltrates in the colon Curative treatment amelioration of colitis Mechanisms of action Induction of IL-10 producing macrophages
Mouse DSS colitis
Ruyssers et al., 2009
Schistosoma mansoni soluble worm proteins (SmSWP)
Trematode Mouse TNBS colitis
Diminished Th1 response (IFN- mRNA expression), diminished Th17 response (IL-17 mRNA expression), augmented Treg response (IL-10, TGF- mRNA expression) Not specied
Ruyssers et al., 2009
Ancylostoma caninum excretory/secretory proteins (AcES) Trichinella spiralis antigen
Nematode
Mouse TNBS colitis
Curative treatment: amelioration of colitis Preventive treatment: attenuation of colitis Preventive and curative treatment: attenuation of colitis Preventive treatment: attenuation of colitis Preventive treatment: attenuation of colitis
Motomura et al., 2009 Johnston et al., 2010
Nematode
Mouse DNBS colitis
Augmented Th2 response (IL-13), augmented Treg response (TGF-), downregulation of IL-1 and iNOS Diminished Th1 response (TNF-), augmented Th2 response (IL-4, IL-10), augmented Treg response (IL-10) Augmented Treg response (TGF-, IL-10) diminished Th1 response (TNF- mRNA expression), diminished Th17 response (IL-6 mRNA expression), augmented Treg response (IL-10, TGF- mRNA expression), activation of alternatively activated macrophages Diminished Th1 response (IFN-, TNF-), diminished Th17 response (IL-17), no changes in Th2 and Treg responses Diminished Th1 response (IFN-, TNF-), diminished Th17 response (IL-17), no changes in Th2 and Treg responses Diminished Th1 response (IFN-, TNF-), diminished Th17 response (IL-6), diminished Th2 response (IL-13), augmented Treg response (IL-10, TGF-), requires recruitment of Treg cells and binding with TLR2 No remarkable effects on cytokines Diminished Th1 response (TNF-), no changes in Treg response, IL-10 secreting F4/80+ macrophages Diminished Th1 response (IFN-), diminished Th17 response (IL-17A), IL-4/IL-10 double positive CD4+ T cells, alternatively activated macrophages and eosinophils Diminished Th1 response (IFN- mRNA expression), diminished Th17 response (IL-17A mRNA expression), augmented Th2 response (IL-4 mRNA expression) Diminished Th17 response (IL-17), augmented Th2 response (IL-4)
Hymenolepis diminuta highmolecular-mass extract (HdHMW) Toxascaris leonine galectin-9 homologue (recombinant) (rTl-GAL) Trichinella spiralis 53-kDa protein (recombinant) (rTs-P53)
Cestode
Mouse DNBS colitis
Kim et al., 2010
Nematode
Mouse DSS colitis
Du et al., 2011
Nematode
Mouse TNBS colitis
Cancado et al., 2011
Ancylostoma ceylanicum excretory/secretory products (AcES) Ancylostoma ceylanicum adult worm crude extract (AcAw)
Nematode
Mouse DSS colitis
Cancado et al., 2011
Nematode
Mouse DSS colitis
Cho et al., 2011
Anisakis simplex macrophage migration inhibitory factor-like protein (recombinant) (rAs-MIF)
Nematode
Mouse DSS colitis
Preventive treatment: amelioration of colitis
Bodammer et al., 2011 Jang et al., 2011
Schistosoma mansoni soluble egg antigen (SEA) Clonorchis sinensis type I cystatin (recombinant) (rCsSten-1) Ancylostoma ceylanicum excretory/secretory products (AcES)
Trematode Mouse DSS colitis Trematode Mouse DSS colitis
Curative treatment: no effect on colitis Curative treatment: amelioration of colitis Preventive treatment: protection from colitis
Ferreira et al., 2013
Nematode
Mouse DSS colitis
Heylen et al., 2013
Schistosoma mansoni worm adult proteins (SWAP)
Trematode Mouse CD4+CD25 CD62L+ T cell transfer colitis Trematode Mouse CD4+CD25 CD62L+ T cell transfer colitis
Curative treatment: amelioration of colitis
Heylen et al., 2014
Schistosoma mansoni soluble egg antigen (SEA)
Curative treatment: amelioration of colitis
CD: cluster of differentiation; DNBS: dinitrobenzene sulfonic acid; DSS: dextran sulfate sodium; IFN-: interferon-; IL: interleukin; iNOS: inducible nitric oxide synthase; kDa: kilodalton; TGF-: transforming growth factor-; Th: T helper cells; TLR2: toll-like receptor 2; TNBS: trinitrobenzene sulfonic acid; TNF-: tumor necrosis factor-
10
(Schnoeller et al., 2008; Kim et al., 2010; Cancado et al., 2011; Cho et al., 2011; Jang et al., 2011; Ferreira et al., 2013). However, in a study performed by Bodammer et al. (2011), S. mansoni soluble egg antigen failed to improve DSS colitis. Next to the DSS model the effect of helminthderived molecules was also studied in the DNBS and TNBS model and the CD4+CD25CD62L+ T cell transfer model. TNBS-induced colitis in mice was attenuated by S. mansoni soluble worm proteins (SmSWP) and Ancylostoma caninum excretory/secretory proteins (AcES) and by recombinant T. spiralis 53-kDa glycoprotein (rTs-P53), a dened component of excretory/secretory proteins (Ruyssers et al., 2009; Du et al., 2011). In addition, T. spiralis antigen and a high-molecular-mass fraction of H. diminuta (HdHMW) reduced the severity of DNBS-induced colitis in mice (Motomura et al., 2009; Johnston et al., 2010). Furthermore, we demonstrated that a curative treatment with S. mansoni worm adult proteins (SWAP) or S. mansoni soluble egg antigens (SEA) reduced the severity of colitis induced by the adoptive transfer of CD4+CD25 CD62L+ T cells in immunocompromised mice (Heylen et al., 2013, in press). Thanks to genomics and proteomics, the genomes of helminths are now being unraveled and new helminth-derived proteins with potentially anti-inammatory effects are being identied at an increasing pace (Cantacessi et al., 2011). In addition to the above mentioned molecules tested in animal models of IBD, helminth-derived products are also being tested extensively in other disease models. For example, omega-1 and IPSE/-1, two glycoproteins secreted by S. mansoni eggs, were evaluated in a mouse model of type 1 diabetes, whereas ES-62, a phosphorylcholine-containing glycoprotein secreted by A. viteae, was tested in a mouse model of rheumatoid arthritis (Harnett & Harnett, 2009; Zaccone et al., 2011). Recently McSorley et al. (2013) extensively reviewed a whole range of helminth-derived mediators and their associated immunoregulatory mechanisms. Because it is clear that some helminth-derived molecules have a similar benecial effect as living helminths, there is an increasing interest in these molecules as new promising therapeutics for inammatory and autoimmune diseases. However, there is still no consensus on the exact mechanism of action that underlies this protective effect of helminths or helminth-derived molecules (McSorley et al., 2013; Weinstock & Elliott, 2013). 5. What do we know about the underlying immunological mechanisms of protection? Unraveling the mechanisms of action underlying the helminthmediated anti-inammatory properties is an absolute requirement. It seems that helminths activate several distinct regulatory pathways involving cellular components of both the innate and adaptive immune system to control gut in ammation (McSorley & Maizels, 2012). 5.1. Effect of helminths and their products on innate immunity in inammatory bowel disease models 5.1.1. Dendritic cells DCs, a specialized antigen presenting cell population of the innate immune system, are known as central mediators of immunity and tolerance since they are able to orchestrate other immune cells including T cells, B cells and macrophages (Niess & Reinecker, 2006; Farache et al., 2013). DCs originate in the bone marrow and are present in blood and in tissue. Interestingly, they markedly accumulate in diseased tissue of IBD patients (Silva, 2009). This makes DCs an important cell population to investigate, not only from an immunopathogenic point of view, but also in a therapeutic perspective. Hart et al. (2005) reported that DCs are altered in IBD. More specically, DCs are activated, the expression of pathogen receptors is upregulated and there are more DCs producing proinammatory cytokines (Hart et al., 2005). These changes support the notion that DCs contribute to inammation in IBD. As DCs intervene high in the cascade of the immune response much attention is being
paid to these antigen presenting cells. In IBD, DCs may act by priming abnormal T cell responses to the enteric ora in organized lymphoid tissues, by sustaining T cell reactivity within the inamed mucosa through interaction with T cells, and by functioning as effector cells via the release of proinammatory cytokines (Niess & Reinecker, 2006). There is evidence in mice that DCs can also cause gut inammation in the absence of B and T cells (Abe et al., 2007). On the other hand it was shown that if DCs are ablated before DSS treatment in mice, the colitis was exacerbated (Abe et al., 2007). This suggests that DCs may play a protective role in the initial phases of colitis but can play a pathogenic role at a later time in the disease course (Mann et al., 2013). Because altering DC activity can inuence inammation, it might be attractive, from a therapeutic point of view, to try modulating the DC maturation process. In this way we might be able to induce DC subsets with a more protective/tolerogenic role against inammation. As reviewed by McSorley et al. (2013) there is evidence that DCs become anergic or tolerogenic after stimulation with different helminth products. It was shown (in vitro and in vivo) that treatment of DCs with nematode products suppresses their production of IL-12 and decreases the expression of co-stimulatory molecules and major histocompatibility complex class II molecules (Whelan et al., 2012). Recent studies on intestinal DCs and on DCs in gut-draining mesenteric lymph nodes report an increase of protolerogenic DCs after helminth infection (Balic et al., 2009; Cruickshank et al., 2009; Smith et al., 2011). Thus, there is good evidence that helminthic infection modulates DC activity enabling helminths to control or prevent overt inammation. With regard to IBD, it was recently shown by Weinstock and colleagues that infection with H. polygyrus bakeri alters the function of DCs in the gut, rendering these cells highly tolerogenic, which suppressed inammation in a murine model of colitis (Hang et al., 2010; Blum et al., 2012). They showed that the transfer of DCs isolated from the intestines or mesenteric lymph nodes from H. polygyrus bakeri-infected mice protected immunocompromised mice from the development of colitis induced by the injection of IL-10/ T cells (Hang et al., 2010; Blum et al., 2012). As mentioned, the DCs isolated from H. polygyrus bakeriinfected mice had a tolerogenic phenotype as they lost their ability to produce proinammatory colitogenic cytokines such as IFN- and IL17 after ovalbumin stimulation (Hang et al., 2010; Blum et al., 2012). To our knowledge, this is the only study that reported on the effect of helminthic therapy on DCs in a mouse model of IBD. Intestinal DCs are constantly exposed to the microora and to food antigens and can be exposed to harmful pathogens. As such, it is essential that they immediately react on subtle changes in their microenvironment hence their specialization and plasticity. In addition, recent evidence points towards different DC phenotypes in the ileum and colon with even differences demonstrated between the ascending and descending colon (Mann et al., 2013). Therefore, investigating DCs in the gastrointestinal tract remains a challenge and more profound studies on the inuence of helminthic therapy on DCs in IBD are necessary. 5.1.2. Macrophages The small and large intestines contain the largest number of macrophages in the body and these cells are strategically located directly underneath the epithelial layer, enabling them to sample the intestinal lumen (MacDonald et al., 2011). In steady state, the phenotype of the intestinal macrophages differs from other tissue macrophages in that they can ingest and kill microbes but they do not initiate proinammatory responses, rather they display an anti-inammatory signature producing the immune-regulatory cytokine IL-10 (Denning et al., 2007; BarOn et al., 2011). These properties are essential for maintaining a healthy intestine and immune homeostasis. In IBD, recently much attention is being paid to DCs but it is clear that also macrophages play an essential role in inammation and protective immunity (Qualls et al., 2006; Mowat & Bain, 2011). Macrophages contribute to intestinal inammation during IBD by the release of proinammatory cytokines (Ince & Elliott, 2007). Whether the inammatory
11
macrophages that occur in inammation are resident cells with changed behavior or whether they are newly recruited cells remains to be established (Mowat & Bain, 2011). Macrophages can exist in different activation states (effector M1 or regulator M2 macrophages) which makes them an attractive target for treatment of IBD. It is well known that helminths and their products induce alternatively activated macrophages in response to IL-10 and Th2 cytokines IL-4 and IL-13 (Siracusa et al., 2008; Elliott & Weinstock, 2012b). M2 have regulatory and inhibitory functions and are strong producers of regulatory TGF- and IL-10 that help skewing the immune response away from the proinammatory cascade (Gordon & Martinez, 2010). Several studies focusing on macrophages have been conducted in IBD animal models. Smith et al. (2007) rst reported that infection with S. mansoni prevented DSS-induced colitis in mice by a mechanism dependent on macrophages. Transfer of colon lamina propria macrophages isolated from S. mansoni infected mice protected recipient mice from DSS-induced colitis (Smith et al., 2007). Hunter and colleagues (2010) reported that the severity of DNBS-induced colitis in mice was signicantly reduced by injection of M2 macrophages and that infection with H. diminuta induces M2 macrophages that protect mice from colitis. Other helminth-based studies also identied the M2 macrophages to be responsible for the relief of experimental colitis in animals (Schnoeller et al., 2008; Du et al., 2011; Jang et al., 2011; Broadhurst et al., 2012; Ferreira et al., 2013). As such it is believed that helminths and their products ameliorate gastrointestinal inammation through stimulation of M2 macrophages. This notion is supported by the nding that M2 macrophages are more abundant in colonic biopsies from patients with inactive Crohn's disease compared to patients with active Crohn's disease (Hunter et al., 2010). In general, tolerogenic DCs and alternatively activated macrophages function to block antigen-specic T cell responses, preventing the differentiation of dangerous effector T cells which lead to inammation and disease (Weinstock, 2012; Weinstock & Elliott, 2013). 5.1.3. Other components of the innate immune system: epithelial barrier and innate lymphoid cells Within this review we would like to touch briey on some of the other important players of the innate immune system that may play a role in the prevention of intestinal inammation by helminths but currently represent somewhat of a caveat in our research eld. As described in a previous paragraph, intestinal epithelial barrier function is severely disrupted during IBD (Baumgart & Carding, 2007; Laitman & Dahan, 2012). It was proposed by Wolff et al. (2012) that intestinal helminths may also protect against colitis by enhancement of the mucosal barrier function. The immune response against intestinal helminths (which is aimed at expelling the parasite from the gastrointestinal tract) includes increased mucus secretion, increased epithelial cell turnover and changed composition of the mucus secreted by goblet cells. All these effects can promote mucosal healing and as such restore normal barrier function leading to amelioration of inammation (Wolff et al., 2012). A few studies also show that intestinal helminths alter the bacterial composition of the intestinal ora, which can impact host immunity and can help to maintain intestinal health (Dwinell et al., 1997; Andersson et al., 2003; Hunter & McKay, 2004; Walk et al., 2010; Weinstock, 2012; Wolff et al., 2012; Weinstock & Elliott, 2013). Although this sounds compelling for intestinal helminths, there are helminth species that protect against colitis (e.g. S. mansoni) while living outside the gastrointestinal tract. Furthermore, it still remains to be elucidated whether helminth-derived products that protect against colitis also do so by directly affecting the mucosal barrier. This interesting topic may provide an additional novel mechanism by which helminths and their products protect against intestinal inammation but it denitely calls for more research. Natural killer (NK) cells are part of the innate immune system, because they lack antigen specic receptors on their membrane, but they have been classied as lymphocytes based on their morphology (Vivier
et al., 2011). They are considered the killer cells of the innate immune system and play a role as cytotoxic cells against viral infections and are important in tumor surveillance (Mortha & Diefenbach, 2011). However, the role of NK cells in IBD is less well understood. They are thought to possess both proinammatory and regulatory functions. There is increasing evidence that distinct subsets of NK cells (with changes in activation and cytotoxic activity) are important during the pathogenesis of IBD (Takayama et al., 2010; Yadav et al., 2011). A recent study by Hall et al. (2013) showed that a depletion of NK cells impaired the survival of mice with DSS colitis and this was linked with dramatic increases in colonic damage, leukocyte inltration, and proinammatory proles. The innate lymphocyte lineage is continuously expanding. The family of innate lymphoid cells (ILC) not only comprises NK cells and lymphoid tissue inducer cells (Koyasu & Moro, 2013), but now also incorporates ILC type 1, ILC type 2 and ILC type 3 (see Spits et al., 2013 for an extensive review on these ILC types). Importantly, these different subsets of ILC have cytokine patterns that are similar to the cytokine secretion proles of the different T helper cell subsets (Spits et al., 2013). Changes in ILC responses have been associated with IBD (Hepworth et al., 2013) and ILC producing IL-17 and IFN- are mediating colitis in a mouse model of intestinal inammation (Buonocore et al., 2010). Furthermore, ILCs regulate adaptive immune responses and limit effector CD4+ T cell responses to commensal bacteria (Hepworth et al., 2013). Research on how helminths inuence ILCs in animal models of IBD is lacking but the fact that these cells intervene high in the inammatory cascade and that they have proven regulatory functions makes them highly interesting new targets for treatment of IBD. 5.2. Effect of helminths and their products on the adaptive immune system in inammatory bowel disease models 5.2.1. T cells In Crohn's disease, gastrointestinal inammation is mediated through Th1 and Th17 cells (Moreels & Pelckmans, 2005; Wallace et al., 2014). During helminth infection, the host evokes a strong Th2 immune response (Fig. 3) (Maizels et al., 2004). The release of Th2 cytokines such as IL-4, IL-5 and IL-13 is important in gastrointestinal worm expulsion from the gut. Both IL-4 and IL-13 promote mucus secretion, enhance intestinal smooth muscle contractility and stimulate uid secretion into the lumen. IL-5 is important for the destruction of some larval forms (Weinstock et al., 2005). This Th2 response is broadly characterized by the activation of eosinophils, basophils and mast cells and the production of IgE (Diaz & Allen, 2007). The cytokines produced by Th1 and Th2 cells cross-regulate each other's development and activity (Hunter & McKay, 2004; Khan & Fallon, 2013). Furthermore, Th1 and Th2 cytokines can inhibit Th17 development (Bi et al., 2007). In addition, helminths induce immunosuppressive Treg cells through a variety of different mechanisms (Fig. 3) (McGuirk & Mills, 2002; Cools et al., 2007). In this way, the helminth evoked immune response can counteract the Th1/Th17 response found in patients with Crohn's disease (Fig. 2B). The discovery of the IL-17 pathway was a major breakthrough in the immunopathogenesis of several inammatory conditions (Zhang et al., 2007) as there seems to be an important imbalance in Th17/Treg cells in IBD and other inammatory diseases. Investigation of the effect of helminths and their products on the Th17/Treg pathway in animal models for IBD is extensive (Tables 1 and 3). For example, we have previously shown that treatment with S. mansoni soluble worm proteins (SmSWP) caused a decrease in IL-17 and an increase in the relative expression of IL-10 and TGF- in T cells isolated from the colon of mice with TNBS-induced colitis (Ruyssers et al., 2009). A. ceylanicum adult worm extracts (AcAw) attenuated DSS colitis in mice by downregulating Th1 and Th17 cytokines (Cancado et al., 2011). In accordance, A. caninum excretory/secretory products (AcES) suppress murine TNBS and DSS colitis (Ruyssers et al., 2009; Cancado et al., 2011; Ferreira et al., 2013) and induce IL4+/IL10+ CD4+ T cells in mesenteric
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lymph nodes and colon (Ferreira et al., 2013). An earlier study by Hunter and colleagues (2005) showed the importance of IL-10 in the protection of Hymenolepsis diminuta against DNBS-induced colitis. A role for Treg cells has also been proposed by the group of Weinstock in multiple studies e.g. showing that infection of mice with H. polygyrus bakeri promotes the production of IL-10 and TGF- by lamina propria T cells and induces CD8+ Treg cells (Metwali et al., 2006; Setiawan et al., 2007) and showing that the adoptive transfer of colonic forkhead box p3 (Foxp3)+/IL-10+ Treg cells isolated from H. polygyrus bakeri-infected mice was sufcient to prevent colitis in a mouse model of IBD (Hang et al., 2013). The majority of experimental studies listed in Tables 1 and 3 indicate a downregulation of Th1 and Th17 responses with an essential role of Treg cells in controlling these immune responses. However, the important question of who is regulating the regulators currently remains, hence the continued attention to the innate arm of the immune system.
protective effect of living helminths remains important as it opens new perspectives for the treatment of IBD. Conict of interest statement The authors declare that there are no conicts of interest. The manuscript has not been published elsewhere and is not under consideration elsewhere. Acknowledgment This work was supported by a grant from the Belgian IBD Research and Development (BIRD) group (BIRD Research Grant 2012A) and the legacy Deceunynck (4692). This work was also supported by the FWO through a Research Grant (1515314N) to Nathalie Ruyssers. References
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5.2.2. B cells Within the adaptive immune system, B cells are known as positive regulators of the humoral immune response by the production of antibodies (Fujimoto, 2010). Regulatory B cells suppress immune responses and are important in the regulation of intestinal homeostasis and inhibition of inammatory cascades (Kayama & Takeda, 2012). Helminthic therapy in multiple sclerosis patients led to the production of IL-10 from regulatory B cells resulting in a reduction of inammation (Correale et al., 2008; Ben-Ami Shor et al., 2013). To our knowledge, the role of B cells has not been investigated yet in the eld of helminthic therapy in IBD which leaves another caveat for more research.
6. Conclusions Helminths and their products are able to attenuate chronic inammation in IBD and in other disorders that result from an overly aggressive immune response. Today the use of helminthic therapy for autoimmune disorders is only available in clinical trial settings. More research, both in animal models and well designed and controlled randomized clinical trials, is necessary to validate the treatment and eventually commercialize helminthic or helminth-derived therapy for IBD. This review provided a detailed overview of the experimental and clinical studies investigating the therapeutic potential of helminthbased therapy in IBD and focused on the underlying immunological mechanisms by which helminths and their products provide protection against intestinal inammation. There is solid evidence that helminths and their products induce multiple immunomodulatory pathways in different animal models of IBD, including downregulation of proinammatory cytokines and induction of regulatory cytokines and regulatory T cells. Although many studies have looked at the role of T cells in this eld, the focus is now shifting towards the effect of helminths and their products on cells of the innate immune system. The role of macrophages and dendritic cells is currently being investigated by multiple research groups showing a more regulatory phenotype after helminthic treatment. There is a major gap in our understanding of how helminths inuence intestinal lymphoid cells and whether these cells subsequently contribute to the attenuation of colitis. Therefore, ILCs are an interesting cell population that deserves more attention in future research. Furthermore, knowledge on the role of B cells is limited, leaving interesting opportunities for nding additional mechanisms by which helminths provide protection against IBD. Although our understanding on the benecial effect of helminths and their products on IBD is continuously growing, it is clear that more in-depth research is necessary to further unravel all mechanisms involved. Furthermore, the identi cation and characterization of helminth-derived immunomodulatory molecules that mimic the
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JPT-06663; No of Pages 15

Pharmacology & Therapeutics xxx (2014) xxxxxx

Contents lists available at ScienceDirect

Pharmacology & Therapeutics

Associate editor: P. Holzer

http://dx.doi.org/10.1016/j.pharmthera.2014.02.011 0163-7258/ 2014 Elsevier Inc. All rights reserved.

M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx

M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx

M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx

M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx

M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx

Khan et al., 2002 Elliott et al., 2003

Trichinella spiralis larvae Schistosoma mansoni eggs Schistosoma mansoni larvae

DNBS colitis TNBS colitis

Moreels et al., 2004 Elliott et al., 2004

Trematode Rat Mouse

TNBS colitis IL-10/ colitis DNBS colitis

Heligmosomoides Nematode polygyrus bakeri larvae Hymenolepis diminuta larvae Cestode

Hunter et al., 2005

Hunter et al., 2005 Chen et al., 2005

Hymenolepis diminuta larvae

Chen et al., 2006

Metwali et al., 2006

Appearance of CD8+ regulatory T cells

Trematode Mouse Trematode Mouse Mouse

IL-10/ colitis TNBS colitis

Sutton et al., 2008

Zhao et al., 2009

Ince et al., 2009

Hang et al., 2010

Wang et al., 2010 Melon et al., 2010

Trematode Mouse Nematode Mouse

Wilson et al., 2011

L-10/ colitis IL10/ T cell transfer colitis DSS colitis

Blum et al., 2012

DonskowLysoniewska et al., 2012 Leung et al., 2012

Broadhurst et al., 2012

Macaques Idiopathic monkeys chronic diarrhea

Adisakwattana et al., 2013

Trichinella papuae larvae

Preventive treatment: attenuation of colitis

M. Heylen et al. / Pharmacology & Therapeutics xxx (2014) xxxxxx

Summers et al., 2005a

Summers et al., 2005b

Croese et al., 2006

Sandborn et al., 2013

Mouse DSS colitis

Ruyssers et al., 2009

Schistosoma mansoni soluble worm proteins (SmSWP)

Trematode Mouse TNBS colitis

Ruyssers et al., 2009

Ancylostoma caninum excretory/secretory proteins (AcES) Trichinella spiralis antigen

Mouse TNBS colitis

Motomura et al., 2009 Johnston et al., 2010

Mouse DNBS colitis

Mouse DNBS colitis

Kim et al., 2010

Mouse DSS colitis

Mouse TNBS colitis

Cancado et al., 2011

Mouse DSS colitis

Preventive treatment: attenuation of colitis

Cancado et al., 2011