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Helminth Immunomodulation in Autoimmune Disease

Taylor B. Smallwood, Paul R. Giacomin, Alex Loukas and 3 more

Frontiers in Immunology · 2017 · Review

doi:10.3389/fimmu.2017.00453

Abstract

Helminths have evolved to become experts at subverting immune surveillance. Through potent and persistent immune tempering, helminths can remain undetected in human tissues for decades. Redirecting the immunomodulating "talents" of helminths to treat inflammatory human diseases is receiving intensive interest. Here, we review therapies using live parasitic worms, worm secretions, and worm-derived synthetic molecules to treat autoimmune disease. We review helminth therapy in both mouse models and clinical trials and discuss what is known on mechanisms of action. We also highlight current progress in characterizing promising new immunomodulatory molecules found in excretory/secretory products of helminths and their potential use as immunotherapies for acute and chronic inflammatory diseases.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

Helminths are large multicellular organisms that can be either free living or parasitic. Parasitic helminths comprise the phyla of roundworms (nematodes), flatworms (platyhelminths), tapeworms (cestodes), and flukes (trematodes) and have plagued humans and archaic humans for hundreds of thousands of years. Today, these parasites remain one of the most successful families of infectious agents on the planet, infecting more than one and a half billion people. In humans, heavy infection with parasites can lead to many serious health problems and sometimes even death. However, a small worm burden typically has limited or no pathology and has even been suggested to be commensal to the host.

Ancient Cloakers

Individual hookworms can live in the human intestine for up to 18 years. To achieve this impressive feat, the parasites effectively cloak through multipronged immunomodulation. The principal immune subsystem targeted is T cell surveillance, which determines self from foreign antigens through a vast yet structured in vivo T cell receptor repertoire. Specifically, the parasites stimulate the release of IL-4, IL-5, IL-10, and IL-13, which promotes Th2 polarization (Figure 1). Regulatory T cell (Treg) development is also stimulated during hookworm infection that enhances the cloaking effect through the release of the regulatory cytokines IL-10 and transforming growth factor (TGF) β. In addition, hookworms induce activation of parasite-specific and total immunoglobulin E (IgE) and the mobilization of the innate immune systems including mast cells, eosinophils, and basophils. Indeed, a recent large-scale community deworming study showed that helminths actively decrease immune responsiveness and modulate immune checkpoint expression in infected individuals. The intrinsic talent of parasitic worms to skew the immune response from Th1 to Th2/Treg has led to the idea of using live worms as immunotherapy (helminthic therapy) or, preferably, seeking compounds in helminth secretions for use as immunomodulatory drugs. Indeed, helminthic therapy in animal models and human trials has provided convincing evidence that low-dose inoculation can treat a number of autoimmune diseases.

Increasing Burden of Autoimmune Disease

Autoimmunity is the failure of the immune system to distinguish pathogens from self-antigens resulting in damage to healthy tissue. Today more than 80 autoimmune diseases have been identified, including inflammatory bowel disease (IBD), multiple sclerosis (MS), rheumatoid arthritis (RA), and type 1 diabetes (T1D). Autoimmune diseases are now estimated to affect almost 10% of the world’s population and collectively represent truly massive global disease and financial burdens. Most autoimmune diseases have no cures and are not knowingly preventable. Disconcertingly, for several decades, the developed world has seen steady increasing incidence of autoimmune disease. While genetic predisposition is known to be a key factor in susceptibility, the sudden surge in these diseases over a very short time period cannot be explained by genetics alone, but rather points to variations in environment and/or lifestyle. Two major theories have been put forward to explain this epidemiology including the “hygiene hypothesis” and the “old friends’ hypothesis”.

Dirty Old Friends

The hygiene hypothesis, formulated in 1989, proposed that lower intensities of infections during early childhood could explain the emergence of asthma and hay fever later in life. The study suggested that declining family size, improvements in household amenities, and increases in personal cleanliness reduced opportunities for cross infections in young families, resulting in a more widespread clinical expression of atopic diseases. Over time, this theory has broadened to include a catalog of chronic inflammatory diseases. Indeed, urban migration, increased access to clean water, and improved sanitation have reduced exposure to many infectious agents including helminths. Multiple epidemiological studies have shown an inverse correlation between microorganism exposure and the development of autoimmunity.

Concordantly, the old friends’ hypothesis suggests that various organisms, including helminths and microbiotas, have long coevolved with their mammalian hosts and act as inducers of immunoregulatory circuits. This hypothesis has a sound rationale given that infectious agents, including helminths, are known to be potent modulators of T cell function and that dysregulation of T cell subsets (Th1 and Th17) are fundamental in autoimmune disease processes including MS, RA, and psoriasis. Of note, an inverse association has been observed between the prevalence of certain helminths and autoimmune diseases.

Animal Models of Helminth Therapy

Over the last decades, there have been numerous animal models used to study hookworm therapy for autoimmune disease (IBD, MS, RA, and T1D). Although these individual animal models do not fully reflect the pathology of human disease, the data obtained can be used for safety and at the very least predictive for therapeutic efficacy in humans. The following sections detail current animal models of helminth therapy and therapy with helminth-derived secretory products.

Inflammatory Bowel Disease

Inflammatory bowel disease is characterized by a chronic relapsing inflammatory condition of the gastrointestinal tract. IBD primarily encompasses ulcerative colitis (UC) and Crohn’s disease (CD). IBD pathogenesis is thought to involve dysregulation in mucosal immunity and defects at the mucosal barrier, particularly a “leaky” intestinal epithelial barrier with impaired tight-junction formation can cause mucosal inflammation secondary to luminal antigen uptake. While both diseases are forms of IBD, the autoimmune T cell responses exhibit different biology. CD is driven by a Th1/Th17 response with large amounts of IFNγ, IL-12, and IL-23 playing key roles. In contrast, UC is considered a Th2-mediated disease, where increases in IL-5 and IL-13 drive pathology through chronic inflammation.

Similar to CD, mouse models of experimental colitis trigger a Th1 type immune response, reflected by the infiltration of IFNγ-producing T cells in the colon. There are three types of animal models of IBD. These are broadly divided into (i) chemically induced models; (ii) models with experimentally altered immune responses; and (iii) models with intestinal epithelial defects. Chemically induced colitis models including the trinitrobenzene sulfonic acid (TNBS) model, dinitrobenzene sulfonic acid (DNBS) model, and dextran sodium sulfate (DSS) model are the most common platforms for IBD research. In the TNBS and DNBS models, colitis is induced via intrarectal instillation of the chemicals. In the DSS model, colitis is induced orally. Each model triggers a Th1 pro-inflammatory immune response within the intestine. A second broad model for IBD includes varieties of knockout mice (TGFβ1−/−, IL-10−/−, and STAT3−/−) that aid in the study of innate and adaptive immune responses during disease. These strains also allow for mechanistic investigations during acute or chronic enteritis. For instance; IL-10−/− mice develop spontaneous colitis that is characterized by histological findings similar to those of human IBD. The T cell transfer model has become one of the most widely used models to study pancolitis and chronic transmural inflammation in the intestine. This method involves the adoptive transfer of naïve T cells (CD4+CD25−) into immunocompromised mice. Advantages of this method include early investigation of immunological events associated with the induction of gut inflammation and the ability to study the role of Tregs in inflammation. The final type of animal model of IBD is defective intestinal epithelial responses. Mouse models such as IKK-γ (NEMO), IKK-β, and mdr1a−/− develop spontaneous colitis due to compromised immunity at the epithelial cell wall. Many of these animal models of IBD show that colitis can be attenuated with prior exposure to different helminth species (Table 1). Several of the parasites use the same immune regulatory mechanism, such as a Th2 polarization, which suppresses inflammation. These effects are commonly mediated through increases of cytokines including IL-4, IL-10, and IL-13 production, as well as a decrease in the pro-inflammatory cytokines such as IFNγ and TNFα (Table 1).

Multiple Sclerosis

Characterized by neurodegeneration, MS leads to the severe impairment of mobility, vision, and coordination eventually resulting in paralysis. The primary cause of pathology is a misdirected immune response against the myelin sheath. Damage is mediated by immunoglobulin, complement, and T cell immunity. Experimental autoimmune encephalomyelitis (EAE) is a mouse model of MS characterized by a pro-inflammatory T cell-mediated disease induced by priming with myelin proteins/peptides. CNS autoimmunity in both EAE and MS is mediated by Th1 and Th17 cells. Induction is thought to be dependent on the Th1 cytokine IL-12, playing a central role in macrophage activation and nitric oxide production. Granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-1 are also considered key cytokines involved in the pathogenesis of EAE. GM-CSF is a key cytokine produced by T cells required for susceptibility to EAE. IL-1β/IL-1R signaling in endothelial cells and leukocytes is critical for EAE development and stimulates GM-CSF production. Together the cytokines interact to create a cycle of neuroinflammation in the CNS. Th2 cytokines appear to be protective, suggesting that Th skewing can prevent diseases or decrease disease severity. Akin to IBD, helminthic therapy in the EAE mouse model decreases the progression of EAE through the suppression of Th1 and Th17 cells and induction of Th2 cells, Tregs, and regulatory macrophages (Table 1).

Type 1 Diabetes

Type 1 diabetes is characterized by a progressive cellular infiltration of the pancreas resulting in the destruction of insulin-producing cells. The non-obese diabetic (NOD) mouse provides a model of human disease through mimicking polyuria, glycosuria, weight loss, and lymphocytic infiltration of the islets of Langerhans. At 5 weeks of age, immune infiltration of the pancreas begins, ultimately ending in lymphocyte-directed destruction of β-cells. Pathology is dependent on CD4+ and CD8+ T cells, with the CD4+ population having a Th1 phenotype. Antigen-presenting cells including B cells, dendritic cells (DCs), and macrophages are key mediators of disease through the presentation of self-antigens. Similar to the IBD and EAE models discussed above, helminthic therapy in the NOD mouse also triggers Th2 skewing due to increases in IL-4 and IL-13 expression, ameliorating Th1-mediated disease (Table 1).

Rheumatoid Arthritis

Rheumatoid arthritis is characterized by chronic inflammation in the joints and overexpression of the cytokines TNFα, IL-1, and IL-6. Pathogenesis involves both genetic predisposition and environmental trigger(s). A number of induced and spontaneous mouse models have been developed that recapitulate features of human disease. Both induced and spontaneous models of RA have been shown to benefit from helminthic therapy through decreasing inflammasome activity at the site of disease and the production of Th1 cytokines such as TNFα, while increasing IL-4 and IgG1 production (Table 1).

Inflammatory Bowel Disease

Ten clinical trials indicate that controlled, low-dose helminthic therapy is safe in IBD and related GIT diseases, with some trials showing statistically significant efficacy at endpoint (Table 2). In 2003, an open-label phase 1 trial examined safety by exposing CD and UC patients to pig whipworm ova. Four patients with active CD and three patients with UC were given a single oral dose of live eggs. Patients were routinely monitored using multiple disease and quality of life indexes over a period of 12 weeks. The trial found that all patients improved clinically without any adverse events. While patients improved for a mean duration of approximately 8 weeks, three patients experienced remission relapse 12 weeks after single helminthic therapy. The study suggested that multiple doses may be required to prolong the benefit of treatment. The study also found that there were no significant clinical complications when patients received multiple doses of live eggs at 3-week intervals for 30 weeks. The group followed up with a placebo-controlled trial of 54 UC patients. The pig whipworm arm received an oral dose of live ova at 3-week intervals for 12 weeks. Again, whipworm therapy produced no adverse events. Between the treatment and placebo groups, statistically significant efficacy was observed at 12 weeks in two separate indices in post hoc analysis. One limitation of pig whipworm therapy is that humans are not the natural host and repeated dosing is required to maintain ongoing infection. In addition, given the larvae are invasive, site of infection is unpredictable with potential migration into the lymphatics and/or small blood vessels. The problems of repeated inoculation and unpredictable migration motivated an alternative modality. In 2006, a proof-of-concept study explored human hookworm for the treatment of CD. While both hookworm and whipworm possess parasite lifecycles that require development in the external environment and therefore unable to proliferate directly in the host; the hookworm is adapted to survive in humans and establish a chronic infection that can last for years from a single inoculation. This makes human hookworm an attractive therapeutic, as a defined dose can be controlled and eliminated via anthelmintic therapy. CD patients with longstanding but mostly inactive disease were inoculated with 25 or 50 live hookworm larvae in an initial and reinoculation trial. Disease index for CD patients was unchanged until week 17. After 20 weeks, clinical scores improved and five patients were in remission at week 45.

Two recent human hookworm clinical trials explored the safety and efficacy of hookworm therapy in celiac disease. The first double-blind, placebo-controlled study inoculated patients twice with 15 live hookworm larvae followed by an aggressive oral gluten challenge after patient intestinal infection was established. Experimental infection proved to be safe but did not result in clinical benefit following gluten challenge. Interestingly, follow-up immunological analysis found that hookworm infection altered cellular immunity, through decreasing basal levels of IFNγ and IL-17 in the intestine and altering CD4+ T cell immunity both in the intestine and, interestingly the circulatory system. The second study combined live hookworm larvae inoculation (20 larvae per individual) with desensitization, specifically a sustained gluten microchallenge. Of note, no uninfected controls were used in the study. Escalating gluten challenges were well tolerated and resulted in stabilization or improvement across all tested indices of gluten toxicity. IFNγ-producing intestinal T cells were observed to decrease, while Treg numbers in the epithelium increased significantly. Three human clinical trials for IBD that have been completed are yet to post study results (NCT01433471, NCT01576471, and NCT01279577) (Table 2). A larger phase 1b dose-ranging hookworm trial for celiac disease treatment is underway (NCT02754609) (Table 2).

Multiple Sclerosis

Six clinical trials in MS have been completed or are in progress for helminthic therapy (Table 2). In 2007, a prospective study of MS patients who were recently positive for parasitic infections (and negative for the 2 previous years) were followed over approximately 5 years via disease score and immunomonitoring. The study found significantly lower disease scores and lower numbers of disease exacerbations in helminth-infected patients. Compared with uninfected patients, myelin basic protein-specific T cells in the peripheral blood showed increased IL-10 and TGFβ production and decreased IL-12 and IFNγ production. Increased success of in vitro cloning efficacy of Tregs was also noted in infected MS patients when compared with uninfected patients. A succeeding study followed the same relapsing–remitting MS patients with natural parasitic infections from the previous study for approximately 7 years. During the course of study, four MS patients received anthelmintic treatment due to worsening symptoms associated with infection. Posttreatment, there was a significant increase in disease score in these individuals accompanied by a permanent alteration of immune phenotype in the circulatory system (decreases in IFNγ-secreting cells and absolute Treg numbers). Asymptomatic, persistently infected patients maintained a significantly lower disease score across the monitoring period. It was speculated that helminths induce regulatory networks that could explain environment-related epidemiology of disease.

The first helminthic therapy trial for MS was published in 2011. Here, five MS patients were given repeated oral doses of pig whipworm for 12 weeks in a baseline versus treatment-controlled exploratory trial. Results revealed that helminthic therapy was well tolerated, and some favorable trends were observed in disease scoring. Increases in serum IL-4 and IL-10 levels were noted in four of the five patients. The second helminthic therapy trial for MS was published in 2015. Here, 10 MS patients were given repeated oral doses of pig whipworm for 12 weeks. Treatment was well tolerated with only mild and self-limiting adverse events. However, no positive effect on disease activity was observed, and there was no alteration in the examined immune biomarkers in the peripheral blood. For both pig whipworm trials, it is currently unknown if the relatively short infection period of 12 weeks is sufficient time to initiate clinical efficacy. Several phase 1/2 clinical trials using pig whipworm or hookworm are currently recruiting or ongoing (Table 2). In addition to IBD and MS, two helminthic therapy trials have been conducted for the treatment of other autoimmune disease such as psoriasis and RA (Table 2). However, a number of trails for MS (NCT01413243 and NCT00630383), psoriasis (NCT01948271 and NCT02011269), and RA (EUCTR2011-006344-71-DE) have been terminated or withdrawn prior to enrollment due to supersession by another study, possessing a lack of efficacy or an unknown cause.

Helminthic therapy is not without controversy. Direct treatment with living worms could cause pathology. Furthermore, the idea of being infected with a living parasite may be a difficult task for many patients. With these limitations in mind, immunomodulatory proteins and peptides secreted by helminths have become a more attractive target for drug development. Here, the use of immunomodulatory drugs derived from helminth molecule “blueprints” would provide a safer and more controllable therapeutic modality.

Immune Modulating Excretory Secretory Products

Excretory/secretory (ES) products are the primary interface between parasitic worms and their hosts. ES products contain a mixture of proteins, glycoproteins, and small molecular weight compounds that are secreted from the oral openings or outer body surfaces. ES products are essential for helminth survival/propagation, allowing the parasites to evade immune surveillance. While a number of studies have reported the benefits of ES products in treating autoimmune diseases in mouse models, to date, only a few worm-derived immunomodulatory macromolecules and recombinant proteins have been characterized in depth. Likewise, ES proteins investigated to date represent only an infinitely small slice of the bioactive compounds found in the complex fluids of helminths. There have been multiple inventories of ES proteins generated from different types of parasitic worms including Fasciola hepatica, Trichinella spiralis, Haemonchus contortus, Brugia malayi, Teladorsagia circumcincta, Schistosoma mansoni, and Ancylostoma caninum. Many studies focus on higher molecular weight proteins (>5 kDa), and there is a notable absence of research on lower MW products (1–5 kDa). Large-scale sequencing projects have revealed the presence of peptides within the genome/transcriptome of Necator americanus and Ancylostoma ceylanicum. In particular, a group of peptides highly expressed in hookworm species exhibit sequence/structural homology to the Stichodactyla helianthus toxin (ShK) family of peptides (referred to as ShKT domains).

Excretory/Secretory-62

Excretory/secretory-62 is a phosphorylcholine (PC)-containing glycoprotein from the ES of the rodent nematode Acanthocheilonema viteae. ES-62 is known to inhibit the activation of B cells and T cells and has also been found to polarize antibody production through increased serum levels of IgG1 but not IgG2a. ES-62 affects B cells by stimulating the regulatory cytokine IL-10 and inducing a hyperresponsiveness to antigen. Due to its immunomodulatory potential, ES-62 was tested in an induced RA mouse model and was found to reduce disease severity and progression when administered following disease onset. ES-62 was also therapeutically effective in a mouse model of systemic lupus erythematosus (SLE). Recently, two small synthetic molecule analogs, based on the active PC-moiety, have been shown to be effective in the mouse models of RA and SLE.

Neutrophil Inhibitory Factor (NIF)

Neutrophil inhibitory factor (NIF) is a glycoprotein from the ES of the canine hookworm A. caninum. NIF selectively binds the CD11b/CD18 complex, a pattern recognition receptor found on polymorphonuclear leukocytes. When activated, the complex plays an essential role in immune clearance through the facilitation of neutrophil adhesion to the endothelium, transmigration across the epithelia and phagocytosis of opsonized targets. Binding of NIF to CD11b/CD18 antagonizes function, making the molecule a potential candidate for treating acute and destructive inflammatory processes such as cerebral ischemic injury. In a phase 2 safety study on acute stroke patients, NIF was well tolerated over a wide dose range. This led to a study in acute ischemic stroke patients where it was hypothesized that NIF may improve neurological recovery through inhibition of neutrophil migration. However, NIF did not show improved clinical outcome, and the study was terminated. Since then there has been a number of animal models demonstrating the potential benefits of NIF in acute inflammatory diseases such as allergic lung inflammation and diabetic retinopathy. Interestingly, evidence of homologous NIF proteins has been reported in other parasites including F. hepatica.

Migration Inhibitory Factor (MIF)

Macrophage migration inhibitory factor (MIF), a human cytokine homolog, is from the ES of human-tropic nematodes. Paradoxically, mammalian MIF is thought to be pro-inflammatory and involved in a number of inflammatory diseases including asthma, RA, IBD, and psoriasis. Two secretory MIF homologs have been identified in nematodes: MIF-1 and MIF-2, possessing 40% and 27% identity with the mammalian protein, respectively. It has been shown that helminth-derived MIF interacts with the ubiquitously expressed antigen presentation protein CD74, suggesting a role in immunomodulation. Mammalian MIF has been found to influence macrophage migration, T cell activation, NK cell activation, and immunoglobulin synthesis, leading to the amplification of inflammatory responses. In contrast, studies on MIF-2, isolated from the nematode Anisakis simplex, have shown amelioration of disease in a DSS-induced colitis model and an allergic airway inflammation model. The effect is mediated through Treg induction.

Cystatins

Cystatins are a group of immunomodulatory proteins found in helminth ES products. Cystatins, along with stefins and kininogens, belong to a superfamily of cysteine protease inhibitors found across metazoan and plant taxa. Cysteine protease inhibitors are responsible for various biological and pathological processes including protein catabolism, antigen processing, and inflammation. Helminth-derived cystatins have been described in many parasite species including Onchocerca volvulus, B. malayi, Nippostrongylus brasiliensis, and A. viteae. These proteins produced by helminths have been found to target monocytes/macrophages both in vivo and in vitro, triggering the release of IL-10 that suppresses inflammatory T cells. The cystatin from A. viteae was found to suppress both DSS-induced colitis and allergic lung inflammation in mice. In a murine model of asthma, treatment with recombinant cystatin prevented Th2 development of disease. Compared with controls, treated mice has significantly reduced eosinophil recruitment, reduced numbers of autoimmune T cells, reduced IL-4, and reduced total IgE. In a murine model of colitis, cystatin-treated mice showed significant decreases in inflammatory index and reduced epithelial damage compared to controls. The mechanism of action in both disease models was mediated by macrophages and IL-10 dependent. The immunomodulating effects of cystatins have also been examined in pig intestinal inflammation, where pigs treated with transgenic probiotic-secreting A. vitaea cystatin possessed a significantly reduced inflammatory score and reduced infiltration of immune cells in the colon compared with controls.

Helminth Defense Molecules (HDMs)

Helminth defense molecules (HDMs) are a newly discovered family of secreted immunomodulatory proteins that share biochemical and structural characteristics with the mammalian “cathelicidin-like” host defense peptides (HDP). HDPs are found in both the animal and plant kingdoms and play important roles in innate immune defense against parasites, fungi, bacteria, and viruses. HDMs within helminth ES are thought to minimize excessive inflammation, which helps the survival of the host and in turn survival of the parasite. FhHDM-1 is a HDM secreted by the trematode F. hepatica that adopts an α-helical structure. FhHDM-1 binds LPS and inhibits interaction with TLRs on macrophages. The protein has been shown to protect mice from LPS-induced inflammation and, when mixed with LPS, significantly reduces TNFα and IL-1β levels in circulation. Mechanistically, FhHDM-1 works by preventing NLRP3 inflammasome activation in macrophages through inhibiting endolysosomal acidification.

P28GST

P28GST is a glutathione S-transferase secreted by the platyhelminth blood fluke S. mansoni. P28GST modulates mucosal immunity in mice and humans by increasing Th2 cytokine production. Encouragingly, immunization using a recombinant P28GST protein was as effective as helminthic therapy in reducing colitis in the TNBS model; however, a pro-Th2 adjuvant was essential for activity. P28GST treatment produced lower local and systemic levels of IL-5 and IL-13 and encouraged eosinophil trafficking, which was crucial for therapeutic effect. P28GST has already successfully undergone phase 1 clinical trials for safety and immunogenicity studies (NCT01512277) and is currently in a phase 2 trial in CD (NCT02281916) (Table 2).

Anti-inflammatory Protein-2 (AIP-2)

Anti-inflammatory protein-2 (AIP-2) is derived from the ES of the canine hookworm A. caninum. Hookworm ES products have been shown to be protective in mouse models of colitis. AIP-2 was found to be one of the most abundant proteins in the hookworm ES proteome, and it was recently demonstrated that intranasal delivery of recombinant AIP-2 protein could suppress airway inflammation in a mouse model of asthma and suppress antigen-specific T cell proliferation in human subjects allergic to house dust mite using in vitro stimulation. Mechanistic studies showed that AIP-2 is primarily captured by mesenteric DCs and that therapeutic effect was dependent on both DCs and Tregs. In contrast to P28GST, AIP-2 suppressed eosinophil infiltration into the lungs, the site of pathology.

TGFβ Pathway Manipulation

TGFβ is a potent regulatory cytokine important in lymphocyte and myeloid cell differentiation and function system. In particular, TGFβ is a key player in the induction of immunological tolerance and production can be influenced by several mechanisms of parasite infection, including host homeostasis, pathogen-triggered TGFβ production, and parasite mimicry. TGFβ homologs/orthologs/ligands have been characterized from several species of helminth including A. caninum, B. malayi, F. hepatica, Heligmosomoides polygyrus, and the Schistosoma genus. In the gut, the induction of regulatory cytokines such as TGFβ is important in suppressing colitis. A study using transgenic mice with T cell-specific defects in TGFβ signaling developed spontaneous colitis. Here, infection with H. polygyrus did not prevent colitis or dampen mucosal Th1 responsiveness, indicating an essential role of T cell TGFβ signaling in regulating mucosal T cell responses.

Prostaglandin (PG) Homologs

Prostaglandin E2 belongs to a family of autocrine and paracrine acting lipids, which in mammals are known to regulate many immune responses. Several reports have described that different helminth species including S. mansoni, T. taeniaeformis, and B. malayi produce PG homologs. A recent study identified a PGE2 homolog as a major component of Trichuris suis ES and suggests that secretion of this homeostatic factor contributes to protective potential in inflammatory diseases. PGE2 directs the immunologic balance away from Th1 responses toward a Th2 type response by modulating DC polarization. PGE2 can also promote resolution of inflammation and subsequent tissue repair with evidence showing regeneration of epithelial crypts after DSS intestinal injury.

ShK

ShkT domains are relatively short peptides, 36–42 amino acids in length, containing 6 conserved cysteines and other conserved residues. ShKT domains adopt a fold with two almost perpendicular stretches of helices that are linked by three disulfide bonds that stabilize the structure. ShKTs have been found in both the plant and animal kingdoms suggesting ancient origins; however, the largest family of ShKTs are found in helminths. ShK from the sea anemone S. helianthus was one of the first immune modulating peptides discovered. ShK blocks the voltage-gated potassium channel Kv1.3 at low picomolar concentrations by binding to a shallow vestibule at the outer entrance of the channel, which occludes entrance to the pore. Kv1.3 channels are expressed on the surface of human T cells and are vital for activation by regulating membrane potential and calcium (Ca2+) signaling. Kv1.3high IKCallow channel phenotype is found exclusively in activated human effect memory T cells (TEM), whereas naïve and central memory T cells (TCM) remain Kv1.3low upon activation. In MS, myelin-reactive T cells are predominantly TEM cells, exhibiting the Kv1.3high IKCallow phenotype after activation with myelin antigens. Therefore, selective inhibition of autoreactive TEM cells with disulfide rich Kv1.3 blockers could be a valuable new therapeutic lead for the treatment of MS. A phase 1 clinical trial was conducted to assess safety, tolerability, and pharmacokinetics of the ShK peptide in healthy volunteers (NCT02446340). Given a satisfactory safety profile, a phase Ib trial was recently conducted in psoriasis patients with results yet to be published (NCT02435342) (Table 2).

AcK1 and BmK1

A large family of ShK-related peptides have recently been discovered in helminths, including two peptides known as AcK1 and BmK1. AcK1 is a 51-residue peptide found in the ES of the hookworm A. caninum and the human pathogen A. ceylanicum. BmK1 is a C-terminal domain of a metalloprotease from the ES of B. malayi. Both peptides have been found to adopt helical structures that closely resemble ShK. To overcome problems in folding during de novo production, a truncated version of AcK1 (AcK1t) was designed lacking the first nine N-terminal residues, and an analog of BmK1 (BmK2) was designed based on the ShK-channel interaction surface, differing from the native peptide by five residues. Both analogs fold without difficulty, yielding a well-resolved, hydrophilic-eluting product. AcK1t and BmK2 were found to block Kv1.3 channels in the low-to-mid nanomolar range, while BmK1 was found to block the channel at low micromolar concentrations. AcK1t and BmK2 were found suppress mouse T cell proliferation in vitro and, in human T cells suppress mitogen stimulation. The results of these studies provide evidence that helminth peptides could potentially replace probiotic worm-based therapies to treat TEM-mediated autoimmune diseases such as RA, MS, T1D, and psoriasis. This would avoid complications of live worm therapy, providing a safer and more controllable therapeutic for inflammatory diseases.

The Future of Helminth-Based Therapies

The potential for helminth-based therapies to treat autoimmune diseases have been demonstrated in animal models and clinical trials highlighted in this review. To date, the majority of clinical trials treat patients with live helminths. Justifiably, there are concerns with this method, including the associated health risks of infection with a live pathogen. However, there is the large potential to harness the specific immunomodulatory ES proteins from helminths to develop more traditional “pill”-based treatments. The synthetic production of ES-derived immunomodulators would alleviate concerns associated with live infection, and they can be produced recombinantly in high quantities at relatively low cost. In addition, the molecules could be directly delivered to the site of pathology for diseases such as IBD using probiotic carries that secrete the drug. Large-scale technologies such as genomics, proteomics, and metabolomics have increased the rate of discovery of new helminth-derived immunomodulators from the genome, and there is little doubt many more candidates will be discovered in the coming years.

Conclusion

With the accruing global burden of autoimmune disease, helminths have become of heightened scientific interest due to their ability to activate immunoregulatory circuits and control immunity. There is strong evidence in mouse models that helminthic therapy, ES components, and helminth-derived synthetic molecules can treat and/or prevent inflammatory diseases such as IBD, T1D, MS, RA, and asthma. Thus far, human trials in celiac disease, UC, CD, MS, RA, and psoriasis have established that therapy is safe with some evidence of therapeutic effect. However, results in the first wave of human trials are not as striking as mouse disease models. Discordance in mouse/human translation is certainly not unique to this system, as is well known in other settings for a number of reasons. Of note, a number of the clinical studies conducted to date were not controlled, comprised small sample sizes, and/or did not use human-tropic helminths. Forthcoming trials will directly address these limitations. Going forward, the concurrent development of helminth-derived anti-inflammatory molecules provides many novel opportunities for safer and more controllable therapeutics against chronic inflammatory diseases. Indeed, inclusive efforts in characterizing and mimicking the full immunomodulating abilities of helminths are only in their infancy and much potential exists in this space.

Author Contributions

Drafting and critical revision of the manuscript: TBS, PRG, AL, JPM, RJC, and JJM.

Conflict of Interest Statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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  13. 13.

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    Animal models to study acute and chronic intestinal inflammation in mammals · 2015
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  55. 55.

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  56. 56.

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  57. 57.

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  60. 60.

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  61. 61.

    Driss V El Nady M Delbeke M Rousseaux C Dubuquoy C Sarazin A The schistosome glutathione S-transferase P28GST, a unique helminth protein, prevents intestinal inflammation in experimental colitis through a Th2-type response with mucosal eosinophils. Mucosal Immunol (2016 ) 9:322–35.

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  62. 62.

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  63. 63.

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    Reyes JL Fernando MR Lopes F Leung G Mancini NL Matisz CE IL-22 restrains tapeworm-mediated protection against experimental colitis via regulation of IL-25 expression. PLoS Pathog (2016 ) 12:e1005481.

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  68. 68.

    Ramanan D Bowcutt R Lee SC Tang MS Kurtz ZD Ding Y Helminth infection promotes colonization resistance via type 2 immunity. Science (2016 ) 352:608–12.

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    Elliott DE Setiawan T Metwali A Blum A Urban JF Weinstock JV. Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. Eur J Immunol (2004 ) 34:2690–8.

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  71. 71.

    La Flamme AC Ruddenklau K Backstrom BT. Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect Immun (2003 ) 71:4996–5004.

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    Gruden-Movsesijan A Ilic N Mostarica-Stojkovic M Stosic-Grujicic S Milic M Sofronic-Milosavljevic L. Mechanisms of modulation of experimental autoimmune encephalomyelitis by chronic Trichinella spiralis infection in Dark Agouti rats. Parasite Immunol (2010 ) 32:450–9.

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  73. 73.

    Walsh KP Brady MT Finlay CM Boon L Mills KHG Infection with a helminth parasite attenuates autoimmunity through TGF-β-mediated suppression of Th17 and Th1 responses. J Immunol (2009 ) 183:1577–86.

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  75. 75.

    Cooke A Tonks P Jones FM O’Shea H Hutchings P Fulford AJ Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol (1999 ) 21:169–76.

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    Zaccone P Fehérvári Z Jones FM Sidobre S Kronenberg M Dunne DW Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur J Immunol (2003 ) 33:1439–49.

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    Liu Q Sundar K Mishra PK Mousavi G Liu Z Gaydo A Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL-10-independent mechanisms. Infect Immun (2009 ) 77:5347–58.

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  79. 79.

    Veenstra AA Tang J Kern TS. Antagonism of CD11b with neutrophil inhibitory factor (NIF) inhibits vascular lesions in diabetic retinopathy. PLoS One (2013 ) 8:e78405.

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  80. 80.

    Osada Y Shimizu S Kumagai T Yamada S Kanazawa T. Schistosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of pro-inflammatory mediators. Int J Parasitol (2009 ) 39:457–64.

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  81. 81.
    The inhibitory effect against collagen-induced arthritis by <it>Schistosoma japonicum </it>infection is infection stage-dependent · 2010
    Not checked
  82. 82.

    Rzepecka J Pineda MA Al-Riyami L Rodgers DT Huggan JK Lumb FE Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome. J Autoimmun (2015 ) 60:59–73.

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    Salinas-Carmona MC de la Cruz-Galicia G Perez-Rivera I Solis-Soto JM Segoviano-Ramirez JC Vazquez AV Spontaneous arthritis in MRL/lpr mice is aggravated by Staphylococcus aureus and ameliorated by Nippostrongylus brasiliensis infections. Autoimmunity (2009 ) 42:25–32.

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    Rodgers DT Pineda MA Suckling CJ Harnett W Harnett MM. Drug-like analogues of the parasitic worm-derived immunomodulator ES-62 are therapeutic in the MRL/Lpr model of systemic lupus erythematosus. Lupus (2015 ) 24:1437–42.

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  85. 85.

    Kahana E. Epidemiologic studies of multiple sclerosis: a review. Biomed Pharmacother (2000 ) 54:100–2.

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    Steinman L Assessment of animal models for MS and demyelinating disease in the design of rational therapy. Neuron (1999 ) 24:511–4.

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    Kuchroo VK Sobel RA Laning JC Martin CA Greenfield E Dorf ME Experimental allergic encephalomyelitis mediated by cloned T cells specific for a synthetic peptide of myelin proteolipid protein. Fine specificity and T cell receptor V beta usage. J Immunol (1992 ) 148:3776–82.

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    Goverman J. Autoimmune T cell responses in the central nervous system. Nat Rev Immunol (2009 ) 9:393–407.

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    Leonard JP Waldburger KE Goldman SJ. Prevention of experimental autoimmune encephalomyelitis by antibodies against interleukin 12. J Exp Med (1995 ) 181:381–6.

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    El-Behi M Ciric B Dai H Yan Y Cullimore M Safavi F The encephalitogenicity of T(H)17 cells is dependent on IL-1- and IL-23-induced production of the cytokine GM-CSF. Nat Immunol (2011 ) 12:568–75.

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    Pare A Mailhot B Levesque SA Lacroix S Involvement of the IL-1 system in experimental autoimmune encephalomyelitis and multiple sclerosis: breaking the vicious cycle between IL-1beta and GM-CSF. Brain Behav Immun (2017 ) 62:1–8.

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    Parasitic worms and inflammatory diseases · 2006
    No notice
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    Nakhooda AF Like AA Chappel CI Murray FT Marliss EB. The spontaneously diabetic Wistar rat. Metabolic and morphologic studies. Diabetes (1977 ) 26:100–12.

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    Makino S Kunimoto K Muraoka Y Mizushima Y Katagiri K Tochino Y. Breeding of a non-obese, diabetic strain of mice. Jikken Dobutsu (1980 ) 29:1–13.

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    Zaccone P Hall SW. Helminth infection and type 1 diabetes. Rev Diabet Stud (2012 ) 9:272–86.

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  96. 96.

    Healey D Ozegbe P Arden S Chandler P Hutton J Cooke A. In vivo activity and in vitro specificity of CD4+ Th1 and Th2 cells derived from the spleens of diabetic NOD mice. J Clin Invest (1995 ) 95:2979–85.

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    Garcia-Hernandez MH Gonzalez-Amaro R Portales-Perez DP. Specific therapy to regulate inflammation in rheumatoid arthritis: molecular aspects. Immunotherapy (2014 ) 6:623–36.

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    Caplazi P Baca M Barck K Carano RA DeVoss J Lee WP Mouse models of rheumatoid arthritis. Vet Pathol (2015 ) 52:819–26.

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  99. 99.

    Summers RW Elliott DE Qadir K Urban JF Thompson R Weinstock JV. Trichuris suis seems to be safe and possibly effective in the treatment of inflammatory bowel disease. Am J Gastroenterol (2003 ) 98:2034–41.

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  100. 100.

    Summers RW Elliott DE Urban JF Jr Thompson RA Weinstock JV. Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology (2005 ) 128:825–32.

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  101. 101.

    Van Kruiningen HJ West AB Potential danger in the medical use of Trichuris suis for the treatment of inflammatory bowel disease. Inflamm Bowel Dis (2005 ) 11:515

    Not in our library10.1097/01.mib.0000160369.47671.a2

  102. 102.

    Croese J O’Neil J Masson J Cooke S Melrose W Pritchard D A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut (2006 ) 55:136–7.

    Not in our library10.1136/gut.2005.079129

  103. 103.

    Mortimer K Brown A Feary J Jagger C Lewis S Antoniak M Dose-ranging study for trials of therapeutic infection with Necator americanus in humans. Am J Trop Med Hyg (2006 ) 75:914–20.

    Not in our library10.4269/ajtmh.2006.75.914

  104. 104.

    Croese J Giacomin P Navarro S Clouston A McCann L Dougall A Experimental hookworm infection and gluten microchallenge promote tolerance in celiac disease. J Allergy Clin Immunol (2015 ) 135:508–16.

    Not in our library10.1016/j.jaci.2014.07.022

  105. 105.
    Effect of Hookworm Infection on Wheat Challenge in Celiac Disease – A Randomised Double-Blinded Placebo Controlled Trial · 2011
    No notice
  106. 106.

    McSorley HJ Gaze S Daveson J Jones D Anderson RP Clouston A Suppression of inflammatory immune responses in celiac disease by experimental hookworm infection. PLoS One (2011 ) 6:e24092.

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  107. 107.

    Sandborn WJ Elliott DE Weinstock J Summers RW Landry-Wheeler A Silver N Randomised clinical trial: the safety and tolerability of Trichuris suis ova in patients with Crohn’s disease. Aliment Pharmacol Ther (2013 ) 38:255–63.

    Not in our library10.1111/apt.12366

  108. 108.

    Correale J Farez M. Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol (2007 ) 61:97–108.

    Not in our library10.1002/ana.21067

  109. 109.

    Correale J Farez MF. The impact of parasite infections on the course of multiple sclerosis. J Neuroimmunol (2011 ) 233:6–11.

    Not in our library10.1016/j.jneuroim.2011.01.002

  110. 110.

    Fleming JO Isaak A Lee JE Luzzio CC Carrithers MD Cook TD Probiotic helminth administration in relapsing-remitting multiple sclerosis: a phase 1 study. Mult Scler (2011 ) 17:743–54.

    Not in our library10.1177/1352458511398054

  111. 111.

    Voldsgaard A Bager P Garde E Akeson P Leffers AM Madsen CG Trichuris suis ova therapy in relapsing multiple sclerosis is safe but without signals of beneficial effect. Mult Scler (2015 ) 21:1723–9.

    Not in our library10.1177/1352458514568173

  112. 112.

    Fleming JO Weinstock JV. Clinical trials of helminth therapy in autoimmune diseases: rationale and findings. Parasite Immunol (2015 ) 37:277–92.

    Not in our library10.1111/pim.12175

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    Crompton DW. The public health importance of hookworm disease. Parasitology (2000 ) 121(Suppl):S39–50.

    Not in our library10.1017/s0031182000006454

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    Mulvenna J Hamilton B Nagaraj SH Smyth D Loukas A Gorman JJ. Proteomics analysis of the excretory/secretory component of the blood-feeding stage of the hookworm, Ancylostoma caninum. Mol Cell Proteomics (2009 ) 8:109–21.

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  115. 115.

    Morphew RM Wright HA LaCourse EJ Woods DJ Brophy PM. Comparative proteomics of excretory–secretory proteins released by the liver fluke Fasciola hepatica in sheep host bile and during in vitro culture ex host. Mol Cell Proteomics (2007 ) 6:963–72.

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    Robinson MW Greig R Beattie KA Lamont DJ Connolly B. Comparative analysis of the excretory–secretory proteome of the muscle larva of Trichinella pseudospiralis and Trichinella spiralis. Int J Parasitol (2007 ) 37:139–48.

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    Yatsuda AP Krijgsveld J Cornelissen AW Heck AJ de Vries E. Comprehensive analysis of the secreted proteins of the parasite Haemonchus contortus reveals extensive sequence variation and differential immune recognition. J Biol Chem (2003 ) 278:16941–51.

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    Hewitson JP Harcus YM Curwen RS Dowle AA Atmadja AK Ashton PD The secretome of the filarial parasite, Brugia malayi: proteomic profile of adult excretory–secretory products. Mol Biochem Parasitol (2008 ) 160:8–21.

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    Craig H Wastling JM Knox DP. A preliminary proteomic survey of the in vitro excretory/secretory products of fourth-stage larval and adult Teladorsagia circumcincta. Parasitology (2006 ) 132:535–43.

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    Cass CL Johnson JR Califf LL Xu T Hernandez HJ Stadecker MJ Proteomic analysis of Schistosoma mansoni egg secretions. Mol Biochem Parasitol (2007 ) 155:84–93.

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  121. 121.

    Cantacessi C Mitreva M Jex AR Young ND Campbell BE Hall RS Massively parallel sequencing and analysis of the Necator americanus transcriptome. PLoS Negl Trop Dis (2010 ) 4:e684.

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    Schwarz EM Hu Y Antoshechkin I Miller MM Sternberg PW Aroian RV. The genome and transcriptome of the zoonotic hookworm Ancylostoma ceylanicum identify infection-specific gene families. Nat Genet (2015 ) 47:416–22.

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    Tang YT Gao X Rosa BA Abubucker S Hallsworth-Pepin K Martin J Genome of the human hookworm Necator americanus. Nat Genet (2014 ) 46:261–9.

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    Harnett W Worms MJ Kapil A Grainger M Parkhouse RME Origin, kinetics of circulation and fate in vivo of the major excretory–secretory product of Acanthocheilonema viteae. Parasitology (1989 ) 99:229–39.

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    Harnett W Harnett MM. Inhibition of murine B cell proliferation and down-regulation of protein kinase C levels by a phosphorylcholine-containing filarial excretory–secretory product. J Immunol (1993 ) 151:4829–37.

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    Harnett MM Deehan MR Williams DM Harnett W. Induction of signalling anergy via the T-cell receptor in cultured Jurkat T cells by pre-exposure to a filarial nematode secreted product. Parasite Immunol (1998 ) 20:551–63.

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    Houston KM Wilson EH Eyres L Brombacher F Harnett MM Alexander J Presence of phosphorylcholine on a filarial nematode protein influences immunoglobulin G subclass response to the molecule by an interleukin-10-dependent mechanism. Infect Immun (2000 ) 68:5466–8.

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    Wilson EH Katz E Goodridge HS Harnett MM Harnett W. In vivo activation of murine peritoneal B1 cells by the filarial nematode phosphorylcholine-containing glycoprotein ES-62. Parasite Immunol (2003 ) 25:463–6.

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    McInnes IB Leung BP Harnett M Gracie JA Liew FY Harnett W Approach targeting articular inflammation using the filarial nematode-derived phosphorylcholine-containing glycoprotein ES-62. J Immunol (2003 ) 171:2127–33.

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    Anbu KA Joshi P. Identification of a 55 kDa Haemonchus contortus excretory/secretory glycoprotein as a neutrophil inhibitory factor. Parasite Immunol (2008 ) 30:23–30.

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    Rieu P Ueda T Haruta I Sharma CP Arnaout MA. The A-domain of beta 2 integrin CR3 (CD11b/CD18) is a receptor for the hookworm-derived neutrophil adhesion inhibitor NIF. J Cell Biol (1994 ) 127:2081–91.

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    Madden K Janczak J McEnroe G Lim D Hartman T Liu D A peptide derived from neutrophil inhibitory factor (NIF) blocks neutrophil adherence to endothelial cells. Inflamm Res (1997 ) 46:216–23.

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    Krams M Lees KR Hacke W Grieve AP Orgogozo J-M Ford GA Acute stroke therapy by inhibition of neutrophils (ASTIN): an adaptive dose-response study of UK-279,276 in acute ischemic stroke. Stroke (2003 ) 34:2543–8.

    Not in our library10.1161/01.str.0000092527.33910.89

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    Schnyder-Candrian S Maillet I Le Bert M Brault L Jacobs M Ryffel B Neutrophil inhibitory factor selectively inhibits the endothelium-driven transmigration of eosinophils in vitro and airway eosinophilia in OVA-induced allergic lung inflammation. J Allergy (Cairo) (2012 ) 2012:245909.

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    Jefferies JR Turner RJ Barrett J. Effect of Fasciola hepatica excretory–secretory products on the metabolic burst of sheep and human neutrophils. Int J Parasitol (1997 ) 27:1025–9.

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    Pastrana DV Raghavan N FitzGerald P Eisinger SW Metz C Bucala R Filarial nematode parasites secrete a homologue of the human cytokine macrophage migration inhibitory factor. Infect Immun (1998 ) 66:5955–63.

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    Zang X Taylor P Wang JM Meyer DJ Scott AL Walkinshaw MD Homologues of human macrophage migration inhibitory factor from a parasitic nematode: gene cloning, protein activity and crystal structure. J Biol Chem (2002 ) 277:44261–7.

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  138. 138.

    Cho Y Jones BF Vermeire JJ Leng L DiFedele L Harrison LM Structural and functional characterization of a secreted hookworm macrophage migration inhibitory factor (MIF) that interacts with the human MIF receptor CD74. J Biol Chem (2007 ) 282:23447–56.

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  139. 139.

    Bacher M Metz CN Calandra T Mayer K Chesney J Lohoff M An essential regulatory role for macrophage migration inhibitory factor in T-cell activation. Proc Natl Acad Sci U S A (1996 ) 93:7849–54.

    Not in our library10.1073/pnas.93.15.7849

  140. 140.

    Apte RS Sinha D Mayhew E Wistow GJ Niederkorn JY. Cutting edge: role of macrophage migration inhibitory factor in inhibiting NK cell activity and preserving immune privilege. J Immunol (1998 ) 160:5693–6.

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  141. 141.

    Mikayama T Nakano T Gomi H Nakagawa Y Liu YC Sato M Molecular cloning and functional expression of a cDNA encoding glycosylation-inhibiting factor. Proc Natl Acad Sci U S A (1993 ) 90:10056–60.

    Not in our library10.1073/pnas.90.21.10056

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    Park SK Cho MK Park H-K Lee KH Lee SJ Choi SH Macrophage migration inhibitory factor homologs of Anisakis simplex suppress Th2 response in allergic airway inflammation model via CD4+CD25+Foxp3+ T cell recruitment. J Immunol (2009 ) 182:6907–14.

    Not in our library10.4049/jimmunol.0803533

  143. 143.

    Hartmann S Kyewski B Sonnenburg B Lucius R. A filarial cysteine protease inhibitor down-regulates T cell proliferation and enhances interleukin-10 production. Eur J Immunol (1997 ) 27:2253–60.

    Not in our library10.1002/eji.1830270920

  144. 144.

    Lustigman S Brotman B Huima T Prince AM McKerrow JH. Molecular cloning and characterization of onchocystatin, a cysteine proteinase inhibitor of Onchocerca volvulus. J Biol Chem (1992 ) 267:17339–46.

    Not in our library

  145. 145.

    Manoury B Gregory WF Maizels RM Watts C. Bm-CPI-2, a cystatin homolog secreted by the filarial parasite Brugia malayi, inhibits class II MHC-restricted antigen processing. Curr Biol (2001 ) 11:447–51.

    Not in our library10.1016/s0960-9822(01)00118-x

  146. 146.

    Dainichi T Maekawa Y Ishii K Zhang T Nashed BF Sakai T Nippocystatin, a cysteine protease inhibitor from Nippostrongylus brasiliensis, inhibits antigen processing and modulates antigen-specific immune response. Infect Immun (2001 ) 69:7380–6.

    Not in our library10.1128/iai.69.12.7380-7386.2001

  147. 147.

    Klotz C Ziegler T Figueiredo AS Rausch S Hepworth MR Obsivac N A helminth immunomodulator exploits host signaling events to regulate cytokine production in macrophages. PLoS Pathog (2011 ) 7:e1001248.

    Not in our library10.1371/journal.ppat.1001248

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    Whelan RA Rausch S Ebner F Günzel D Richter JF Hering NA A transgenic probiotic secreting a parasite immunomodulator for site-directed treatment of gut inflammation. Mol Ther (2014 ) 22:1730–40.

    Not in our library10.1038/mt.2014.125

  149. 149.

    Alvarado R O’Brien B Tanaka A Dalton JP Donnelly S. A parasitic helminth-derived peptide that targets the macrophage lysosome is a novel therapeutic option for autoimmune disease. Immunobiology (2015 ) 220:262–9.

    Not in our library10.1016/j.imbio.2014.11.008

  150. 150.

    Mookherjee N Hancock RE. Cationic host defence peptides: innate immune regulatory peptides as a novel approach for treating infections. Cell Mol Life Sci (2007 ) 64:922–33.

    Not in our library10.1007/s00018-007-6475-6

  151. 151.
    A Family of Helminth Molecules that Modulate Innate Cell Responses via Molecular Mimicry of Host Antimicrobial Peptides · 2011
    No notice
  152. 152.

    Alvarado R To J Lund ME Pinar A Mansell A Robinson MW The immune modulatory peptide FhHDM-1 secreted by the helminth Fasciola hepatica prevents NLRP3 inflammasome activation by inhibiting endolysosomal acidification in macrophages. FASEB J (2017 ) 31(1):85–95.

    Not in our library10.1096/fj.201500093r

  153. 153.

    Balloul JM Sondermeyer P Dreyer D Capron M Grzych JM Pierce RJ Molecular cloning of a protective antigen of schistosomes. Nature (1987 ) 326:149–53.

    Not in our library10.1038/326149a0

  154. 154.
    Safety and immunogenicity of rSh28GST antigen in humans: phase 1 randomized clinical study of a vaccine candidate against urinary schistosomiasis. · 2012
    Not checked
  155. 155.

    Cancado GG Fiuza JA de Paiva NC Lemos Lde C Ricci ND Gazzinelli-Guimaraes PH Hookworm products ameliorate dextran sodium sulfate-induced colitis in BALB/c mice. Inflamm Bowel Dis (2011 ) 17:2275–86.

    Not in our library10.1002/ibd.21629

  156. 156.

    Navarro S Pickering DA Ferreira IB Jones L Ryan S Troy S Hookworm recombinant protein promotes regulatory T cell responses that suppress experimental asthma. Sci Transl Med (2016 ) 8:362ra143.

    Not in our library10.1126/scitranslmed.aaf8807

  157. 157.

    Letterio JJ Roberts AB. Regulation of immune responses by TGF-beta. Annu Rev Immunol (1998 ) 16:137–61.

    Not in our library10.1146/annurev.immunol.16.1.137

  158. 158.

    Johnston CJ Smyth DJ Dresser DW Maizels RM TGF-beta in tolerance, development and regulation of immunity. Cell Immunol (2016 ) 299:14–22.

    Not in our library10.1016/j.cellimm.2015.10.006

  159. 159.

    Brand AM Varghese G Majewski W Hawdon JM. Identification of a DAF-7 ortholog from the hookworm Ancylostoma caninum. Int J Parasitol (2005 ) 35:1489–98.

    Not in our library10.1016/j.ijpara.2005.07.004

  160. 160.

    Gomez-Escobar N Gregory WF Maizels RM. Identification of tgh-2, a filarial nematode homolog of Caenorhabditis elegans daf-7 and human transforming growth factor beta, expressed in microfilarial and adult stages of Brugia malayi. Infect Immun (2000 ) 68:6402–10.

    Not in our library10.1128/iai.68.11.6402-6410.2000

  161. 161.

    Gomez-Escobar N Lewis E Maizels RM. A novel member of the transforming growth factor-beta (TGF-beta) superfamily from the filarial nematodes Brugia malayi and B. pahangi. Exp Parasitol (1998 ) 88:200–9.

    Not in our library10.1006/expr.1998.4248

  162. 162.

    Japa O Hodgkinson JE Emes RD Flynn RJ TGF-beta superfamily members from the helminth Fasciola hepatica show intrinsic effects on viability and development. Vet Res (2015 ) 46:29

    Not in our library10.1186/s13567-015-0167-2

  163. 163.

    McSorley HJ Grainger JR Harcus Y Murray J Nisbet AJ Knox DP daf-7-related TGF-beta homologues from trichostrongyloid nematodes show contrasting life-cycle expression patterns. Parasitology (2010 ) 137:159–71.

    Not in our library10.1017/s0031182009990321

  164. 164.
    TGF-β Signaling Controls Embryo Development in the Parasitic Flatworm Schistosoma mansoni · 2007
    No notice
  165. 165.

    Freitas TC Jung E Pearce EJ. A bone morphogenetic protein homologue in the parasitic flatworm, Schistosoma mansoni. Int J Parasitol (2009 ) 39:281–7.

    Not in our library10.1016/j.ijpara.2008.08.001

  166. 166.

    Liu R Zhao QP Ye Q Xiong T Tang CL Dong HF Cloning and characterization of a bone morphogenetic protein homologue of Schistosoma japonicum. Exp Parasitol (2013 ) 135:64–71.

    Not in our library10.1016/j.exppara.2013.05.016

  167. 167.

    Fusco AC Salafsky B Kevin MB. Schistosoma mansoni: eicosanoid production by cercariae. Exp Parasitol (1985 ) 59:44–50.

    Not in our library10.1016/0014-4894(85)90055-4

  168. 168.

    Leid RW McConnell LA. PGE2 generation and release by the larval stage of the cestode, Taenia taeniaeformis. Prostaglandins Leukot Med (1983 ) 11:317–23.

    Not in our library10.1016/0262-1746(83)90043-4

  169. 169.

    Liu LX Serhan CN Weller PF. Intravascular filarial parasites elaborate cyclooxygenase-derived eicosanoids. J Exp Med (1990 ) 172:993–6.

    Not in our library10.1084/jem.172.3.993

  170. 170.

    Belley A Chadee K. Eicosanoid production by parasites: from pathogenesis to immunomodulation? Parasitol Today (1995 ) 11:327–34.

    Not in our library10.1016/0169-4758(95)80185-5

  171. 171.

    Kalinski P. Regulation of immune responses by prostaglandin E2. J Immunol (2012 ) 188:21–8.

    Not in our library10.4049/jimmunol.1101029

  172. 172.

    Nakanishi M Rosenberg DW. Multifaceted roles of PGE2 in inflammation and cancer. Semin Immunopathol (2013 ) 35:123–37.

    Not in our library10.1007/s00281-012-0342-8

  173. 173.

    Levy BD Clish CB Schmidt B Gronert K Serhan CN. Lipid mediator class switching during acute inflammation: signals in resolution. Nat Immunol (2001 ) 2:612–9.

    Not in our library10.1038/89759

  174. 174.

    Cohn SM Schloemann S Tessner T Seibert K Stenson WF. Crypt stem cell survival in the mouse intestinal epithelium is regulated by prostaglandins synthesized through cyclooxygenase-1. J Clin Invest (1997 ) 99:1367–79.

    Not in our library10.1172/jci119296

  175. 175.

    Dauplais M Lecoq A Song J Cotton J Jamin N Gilquin B On the convergent evolution of animal toxins. Conservation of a diad of functional residues in potassium channel-blocking toxins with unrelated structures. J Biol Chem (1997 ) 272:4302–9.

    Not in our library10.1074/jbc.272.7.4302

  176. 176.

    Rangaraju S Khoo KK Feng Z-P Crossley G Nugent D Khaytin I Potassium channel modulation by a toxin domain in matrix metalloprotease 23. J Biol Chem (2010 ) 285:9124–36.

    Not in our library10.1074/jbc.m109.071266

  177. 177.

    Chhabra S Chang SC Nguyen HM Huq R Tanner MR Londono LM Kv1.3 channel-blocking immunomodulatory peptides from parasitic worms: implications for autoimmune diseases. FASEB J (2014 ) 28:3952–64.

    Not in our library10.1096/fj.14-251967

  178. 178.

    Castañeda O Sotolongo V Amor AM Stöcklin R Anderson AJ Harvey AL Characterization of a potassium channel toxin from the Caribbean sea anemone Stichodactyla helianthus. Toxicon (1995 ) 33:603–13.

    Not in our library10.1016/0041-0101(95)00013-c

  179. 179.

    Pennington MW Byrnes ME Zaydenberg I Khaytin I de Chastonay J Krafte DS Chemical synthesis and characterization of ShK toxin: a potent potassium channel inhibitor from a sea anemone. Int J Pept Protein Res (1995 ) 46:354–8.

    Not in our library10.1111/j.1399-3011.1995.tb01068.x

  180. 180.

    DeCoursey TE Chandy KG Gupta S Cahalan MD. Voltage-gated K+ channels in human T lymphocytes: a role in mitogenesis? Nature (1984 ) 307:465–8.

    Not in our library10.1038/307465a0

  181. 181.

    Chandy KG DeCoursey TE Cahalan MD McLaughlin C Gupta S. Voltage-gated potassium channels are required for human T lymphocyte activation. J Exp Med (1984 ) 160:369–85.

    Not in our library10.1084/jem.160.2.369

  182. 182.

    Wulff H Calabresi PA Allie R Yun S Pennington M Beeton C The voltage-gated Kv1.3 K(+) channel in effector memory T cells as new target for MS. J Clin Invest (2003 ) 111:1703–13.

    Not in our library10.1172/jci16921

  183. 183.

    Beeton C Wulff H Standifer NE Azam P Mullen KM Pennington MW Kv1.3 channels are a therapeutic target for T cell-mediated autoimmune diseases. Proc Natl Acad Sci U S A (2006 ) 103:17414–9.

    Not in our library10.1073/pnas.0605136103

  184. 184.

    Conrad C Boyman O Tonel G Tun-Kyi A Laggner U de Fougerolles A Alpha1beta1 integrin is crucial for accumulation of epidermal T cells and the development of psoriasis. Nat Med (2007 ) 13:836–42.

    Not in our library10.1038/nm1605

  185. 185.

    Kivisakk P Mahad DJ Callahan MK Sikora K Trebst C Tucky B Expression of CCR7 in multiple sclerosis: implications for CNS immunity. Ann Neurol (2004 ) 55:627–38.

    Not in our library10.1002/ana.20049

  186. 186.

    Steinfelder S O’Regan NL Hartmann S. Diplomatic assistance: can helminth-modulated macrophages act as treatment for inflammatory disease? PLoS Pathog (2016 ) 12:e1005480.

    Not in our library10.1371/journal.ppat.1005480

  187. 187.

    Whelan RA Rausch S Ebner F Gunzel D Richter JF Hering NA A transgenic probiotic secreting a parasite immunomodulator for site-directed treatment of gut inflammation. Mol Ther (2014 ) 22:1730–40.

    Not in our library10.1038/mt.2014.125

  188. 188.

    Mak IW Evaniew N Ghert M. Lost in translation: animal models and clinical trials in cancer treatment. Am J Transl Res (2014 ) 6:114–8.

    Not in our library

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