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Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases by Bolstridge, et al.

Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases by Bolstridge, et al.



This review updates a previous one (Reddy and Fried, Parasitol Res 104:217–221,2009) on Crohn’s and other autoimmune diseases and helminth therapy. This review considers the use of various ...

This review updates a previous one (Reddy and Fried, Parasitol Res 104:217–221,2009) on Crohn’s and other autoimmune diseases and helminth therapy. This review considers the use of various helminths or their worm products to treat the following autoimmune diseases: Inflammatory Bowel Disease, Multiple Sclerosis, Rheumatoid Arthritis, Type-1 Diabetes, and Asthma and allergic disorders.



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    Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases by Bolstridge, et al. Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases by Bolstridge, et al. Document Transcript

    • Chapter 9Helminth Therapy to Treat Crohn’s and OtherAutoimmune DiseasesJeff Bolstridge, Bernard Fried, and Aditya ReddyAbstract This review updates a previous one (Reddy and Fried, Parasitol Res104:217–221, 2009) on Crohn’s and other autoimmune diseases and helminththerapy. Our review considers the use of various helminths or their worm productsto treat the following autoimmune diseases: Inflammatory Bowel Disease, MultipleSclerosis, Rheumatoid Arthritis, Type-1 Diabetes, and Asthma and allergic disor-ders. The use of the following helminths or their worm products are consideredin this review: the nematodes Trichuris suis, Necator americanus, Heligomoso-moides polygyrus, Trichinella spiralis, Ancanthocheilonema viteae, Ascaris suum,Nippostrongylus brasiliensis, Syphacia obvelata, Dirofilaria immitis, Litomosoidessigmodontis; the cestodes Hymenolepis diminuta and Taenia crassiceps; and thetrematodes Schistosoma mansoni, Schistosoma japonicum, and Fasciola hepatica.Our review discusses the potential role of worm products rather than live worms infuture studies using helminths to treat autoimmune diseases.9.1 IntroductionThis review updates the previous ones by Reddy and Fried (2007, 2009) on the useof helminths to treat Crohn’s and other autoimmune diseases. Helminth (or worm)therapy can be defined as the use of larval or adult helminths or products derivedfrom these helminths to treat a disease. The current review considers some of themajor findings in the earlier reviews, but mainly focuses on newer studies notmentioned previously. A current area of study uses worm products to treat autoim-mune diseases as opposed to infection with live worms; the body of literatureconcerned with this new area of research is considered here. This review alsoJ. BolstridgeDepartment of Chemistry, Lafayette College, Easton, PA 18042, USAB. Fried (*) and A. ReddyDepartment of Biology, Lafayette College, Easton, PA 18042, USAe-mail: friedb@lafayette.eduH. Mehlhorn (ed.), Nature Helps..., Parasitology Research Monographs 1, 211DOI 10.1007/978-3-642-19382-8_9, # Springer-Verlag Berlin Heidelberg 2011
    • 212 J. Bolstridge et al.covers helminths and autoimmune diseases not previously discussed in Reddy andFried (2007, 2009). An autoimmune disease is an illness caused by a self-destructive immune systemdamaging its own body tissues. The autoimmune diseases covered in this review areas follows: Inflammatory Bowel Disease (IBD), Multiple Sclerosis, RheumatoidArthritis, Type-1 Diabetes, and Asthma and allergic disorders. The diseases men-tioned in this review are the most important for which helminth therapy has beenshown to be a possible treatment.9.2 Inflammatory Bowel DiseaseIBD is characterized by chronic inflammation of the gastrointestinal tract andincludes ulcerative colitis (UC) and Crohn’s disease (CD) (Braus and Elliott2009). While both UC and CD have the common symptom of periodic bouts ofinflammation, UC is usually limited to the rectum, while CD affects all areas of thegastrointestinal tract (Reddy and Fried 2007). The inflammation presented in CDextends deep into the mucosal lining, commonly leading to abdominal pain anddiarrhea (Reddy and Fried 2007). Genetic and environmental factors play a role inthe development of these severe inflammatory responses (Ruyssers et al. 2009).Countries with low incidence of helminth infection, typically industrialized nations,have relatively high rates of IBD (Alic 2000). The well-known hygiene hypothesissuggests that infection with helminths from an early age reduces the occurrence ofIBD, among other disorders (Reddy and Fried 2007). The key to treating IBD is to induce long-term remission in patients in order torelieve them of their painful symptoms. Corticosteroids and mesalamine are thedrugs of choice for the treatment of IBD, and can induce remission in patients(Ruyssers et al. 2009). Other drug therapies have been developed, but with many ofthese treatment options the patient may still require surgery because of the increas-ing dependency of the patient on the drugs (Ruyssers et al. 2009). Novel therapiesthat reduce the requirement of surgery in patients are needed for people sufferingfrom IBD because of the risks inherent in gastrointestinal surgery. Helminththerapy involves the use of whole larval or adult worms or viable eggs or wormproducts (such as various proteins) to treat a disease. Table 9.1 details the variousdiseases where helminth therapy has undergone experimental trials in animal orhuman models. This table also lists the helminths reported to have beneficial effectson these diseases. Many studies have been conducted using helminth therapy totreat both UC and CD, both in animal and human models. The cytokine profile of CD is characterized by a T helper type 1 (Th1) inflam-matory response (Braus and Elliott 2009). Key developments in CD include intenselocal B cell stimulation, high IgG production, and an uncharacteristically lowsecretory IgA and IgM response (Reddy and Fried 2007). This characteristicresponse is different than in UC, which is thought to be a Th2-type inflammation(Kuijk and Van Die 2010). The complete immune responses to helminth infections
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 213Table 9.1 The use of various helminths or helminth products to treat autoimmune diseasesHelminth used Worm stage or Host used References product usedInflammatory Bowel DiseaseTrichuris suis (N) Egg Humans Elliott et al. (2005), Summers et al. (2005a, b, c, 2006)Hymenolepis Larva Rats, Mice Hunter et al. (2007), Johnston et al. (2010) diminuta (C)Schistosoma Egg Mice Elliott et al. (2003) mansoni (T) Larva Rats, Mice Moreels et al. (2004), Smith et al. (2007) Worm Mice Ruyssers et al. (2010) productsNecator americanus Larva Human Croese et al. (2006) (N)Heligomosomoides Larva Mice Elliott et al. (2004) polygyrus (N)Trichinella Larva Mice Khan et al. (2002), Motomura et al. spiralis (N) (2009)S. japonicum (T) Egg Mice Mo et al. (2007)Multiple sclerosisS. mansoni (T) Larva Mice, Correale and Farez (2007), Correale et al. Humans (2008, 2009), La Flamme et al. (2003) Egg antigens Mice Sewell et al. (2003)S. japonicum (T) Egg antigens Mice Zheng et al. (2008)Fasciola hepatica (T) Larva Mice Walsh et al. (2009)T. spiralis (N) Larva Mice Gruden-Movsesijan et al. (2008)Rheumatoid ArthritisAncanthocheilonema Worm antigen Mice McInnes et al. (2003) viteae (N)S. mansoni (T) Larva Mice Osada et al. (2009)Ascaris suum (N) Worm antigen Rats, Mice Rocha et al. (2008)Nippostrongylus Larva Mice Salinas-Carmona et al. (2009) brasiliensis (N)Syphacia Larva Rat Pearson and Taylor (1975) obvelata (N)Type-1 DiabetesS. mansoni (T) Larva Mice Cooke et al. (1999) Egg antigens Mice Zaccone et al. (2003, 2009)Dirofilaria Worm antigen Mice Imai et al. (2001) immitis (N)Litomosoides Larva Mice H€bner et al. (2009) u sigmodontis (N) Worm antigen Mice H€bner et al. (2009) uH. polygyrus (N) Larva Mice Liu et al. (2009), Saunders et al. (2007)T. spiralis (N) Larva Mice Saunders et al. (2007)Taenia crassiceps (C) Larva Mice Espinoza-Jimenez et al. (2010)Allergic RhinitisS. mansoni (T) Larva Mice Mangan et al. (2004, 2006)S. japonicum (T) Egg antigen Mice Yang et al. (2006) Viable eggs Mice Yang et al. (2006)H. polygyrus (N) Larva Mice Wilson et al. (2005)A. suum (N) Worm antigen Mice Itami et al. (2005)L. sigmodontis (N) Larva Mice Dittrich et al. (2008)C Cestoda; N Nematoda; T Trematoda
    • 214 J. Bolstridge et al.still remain largely unknown (Ehrhardt 1996; Sartor 2006). It is known thathelminths lead to a characteristic Th2-type phenotype with Th2-associated cyto-kines interleukin-4 (IL-4), IL-5, and IL-13 (Fukumoto et al. 2009). IL-33 isproduced by intestinal epithelial cells (IEC) and it is seen in the earliest stages ofinfections (Humphreys et al. 2008). IL-33 is known to bind ST2 receptors, whichare thought to play a role in the Th2 response (Yoshimoto and Nakanishi 2006). Trichuris suis, the pig whipworm, has undergone multiple clinical studies forpatients with IBD, and the results of these studies showed a reduction in diseaseactivity, as measured by a CD activity index, following treatment with T. suis eggs(TSE) (Elliott et al. 2005; Summers et al. 2005a, b, c, 2006). It is thought thatthe domination of the Th2 phenotype due to the helminth overrides the Th1response of the CD inflammation (Weinstock et al. 2005). Patients were exposedto repeated doses of TSE, and these repetitious doses led to concerns about thepotential spread of the larvae in patients (Van Kruiningen and West 2005).Because the patients went into remission after ingestion of TSE future studieson the use of TSE as a realistic and viable treatment option for patients with IBDare warranted. Figure 9.1 shows the life cycle of T. suis. In many of the referencedstudies on pig whipworm, the authors use the term T. suis ova (TSO) rather than 2 3 4 1Fig. 9.1 Life cycle of the nematode Trichuris suis. (1) Unembryonated eggs are passed in thefeces of the vertebrate host. (2) Unembryonated eggs develop into embryonated eggs. (3) The eggsare ingested by the vertebrate host and then hatch into larvae. (4) The larvae develop into male andfemale adult worms
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 215TSE. It should be noted that TSE is the correct term, because the egg has a shell,residual yolk, and an ovum. Hymenolepis diminuta (the rat tapeworm) has been examined for its effect onoxazolone-induced colitis in the rat (Hunter et al. 2007). Hunter et al. (2007) foundthat H. diminuta infection severely worsened the chemically induced Th2 modelcolitis in rats, as measured by macroscopic clinical scores, histologic damagescores, myeloperoxidase and eosinophil peroxidase activity, and cytokine synthe-sis. Independent of colitis, the H. diminuta infection increased the Th2 markersIL-4, IL-5, IL-10, and IL-13 (Hunter et al. 2007). The most interesting result fromthis study is that Hunter et al. (2007) found that H. diminuta can be helpful intreating other chemically induced colitis models. H. diminuta has also been studied in mice with dinitrobenzenesulfonic acid(DNBS) induced colitis (Hunter et al. 2010; Johnston et al. 2010). These studiesfound that infection with H. diminuta alleviated the pathology of the DNBStreatment (Hunter et al. 2010; Johnston et al. 2010). Johnston et al. (2010) foundthat the mice cotreated with DNBS and three intraperitoneal injections of theparasite had decreased levels of tumor necrosis factor-alpha (TNF-a), and increasedlevels of IL-10 and IL-6. Furthermore, cotreated mice that were also administeredanti-IL-10 antibodies showed a slightly blunted effect of H. diminuta on the colitis,suggesting that IL-10 is critical in the use of H. diminuta as a novel therapy forcolitis. The specific factors that allow H. diminuta to alleviate colitis pathologywould be preferable as a treatment rather than the use of the adult worm becausethere would be no risk of worm infection. Studies that identify specific immuno-suppressive factors are needed. Hunter et al. (2010) transferred alternatively acti-vated macrophages (AAMs) from mice infected with H. diminuta to mice withDNBS-induce colitis, and found that AAMs were able to alleviate the pathology ofthe colitis. They did this based on the knowledge that the DNBS/H. diminutacotreatment shows a high expression of arginase-1, a marker for AAMs (Hunteret al. 2010). The promising results from this study suggest that AAM transfer couldbe developed into a viable therapy for patients suffering from IBD. Figure 9.2shows the major stages of the H. diminuta life cycle. Schistosoma mansoni (Fig. 9.3) has been used extensively in studies treatingtrinitrobenzenesulfonic acid (TNBS) colitis in animal models, as a live infection(Moreels et al. 2004; Smith et al. 2007), as a treatment using egg exposure(Elliott et al. 2003), and using soluble worm products (Ruyssers et al. 2010).Elliott et al. (2003) demonstrated a shift from Th1 to Th2 response upon exposureto S. mansoni eggs in TNBS-treated mice, and this resulted in prevention of lethalinflammation. This general shift was also found in studies that used liveS. mansoni adult worms (Moreels et al. 2004; Smith et al. 2007). Ruyssers et al.(2010) found that cotreatment with TNBS and S. mansoni proteins led to theamelioration (measured at day 5 post-cotreatment) of colitis-induced peristalticactivity and gross disease scores as measured by validated inflammation para-meters such as gastric emptying and cytokine profiles. Interestingly, Ruysserset al. (2010) found that S. mansoni had no effect on the cytokine profiles of theTNBS treatment 5 days after cotreatment, which contradicted earlier studies that
    • 216 J. Bolstridge et al. 3 4 2 1Fig. 9.2 Life cycle of the cestode Hymenolepis diminuta. (1) Eggs are passed in the feces of thevertebrate host. (2) Eggs are ingested by an insect intermediate host and oncospheres hatch uponingestion. (3) Oncospheres develop into cysticerci within the insect. (4) The vertebrate host ingeststhe insect (which contains cystercerci), and adult worms develop within the vertebrate hostFig. 9.3 Life cycle of the trematode Schistosoma mansoni. (1) Eggs are passed in the feces of thevertebrate host. (2) Upon contact with fresh water, eggs hatch into miracidia. (3) Miracidiapenetrate into snail tissue and develop into sporocysts. (4) Cercariae are released by the snailhost. (5) Cercariae penetrate through vertebrate skin. They then shed their tails, circulate, anddevelop into male and female adult wormsreported S. mansoni affected cytokine profiles 3 days after cotreatment. This resultimplies that repeated treatments with S. mansoni proteins may be required for theinducement of long-term remission in colitis patients. Other parasites as noted in Table 9.1 have been used in the treatment of IBD.These include Necator americanus (Croese et al. 2006), Heliogomosomoides poly-gyrus (Elliott et al. 2004), Trichinella spiralis (Khan et al. 2002; Motomura et al.
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 2172009), and Schistosoma japonicum (Mo et al. 2007). Most of these studies involvedtreating subjects with experimental or clinical colitis with infection of adult wormsor treatment with live eggs. However, we believe that new studies that use wormproducts rather than whole worms are very important and crucial to the advance-ment of helminth therapy; by not infecting humans with viable eggs or adult wormsthere is minimal risk of worm infection developing in patients. Helminth therapy,particularly with the use of worm-derived products, appears to be promising as afuture treatment option for the millions of people affected by IBD.9.3 Multiple SclerosisMultiple sclerosis (MS) is a neurological disorder that is caused by an inflammatoryresponse against the myelin sheath of a patient’s central nervous system (Correaleand Mauricio 2009). MS is commonly thought to be autoimmune in origin, withself-reactive Th1 and Th17 cells recognizing the myelin sheath (McFarland andMartin 2007). Studies have shown that MS has high rates of incidence in developed,industrialized countries (Kurtzke 2000). This disease is thought to be caused by acombination of genetic and environmental factors, but these factors are unknown atpresent (Correale and Mauricio 2009). Studies on the potential use of helminth therapy as a treatment for MS ofteninvolve the use of mice with experimental autoimmune encephalitis (EAE), whichis a mouse model for this disease (La Flamme et al. 2003; Sewell et al. 2003; Zhenget al. 2008). La Flamme et al. (2003) studied mice with EAE that were infected anduninfected with S. mansoni and found that the infected mice had a blunted inflam-matory response as measured by the cellular composition of mouse spinal cords andbrains. In conjunction with these results, they found that the infected mice hadlower levels of IL-12p40, a Th1-associated cytokine (La Flamme et al. 2003).Similarly, Sewell et al. (2003) found decreased interferon-gamma (IFN-g), aTh1-associated cytokine, and an increased presence of Th2-related cytokinesIL-4, IL-10, and transforming growth factor-beta (TGF-b). Furthermore, infectedmice which were deficient in the signal transducer and activator of transcription 6, agene that plays a critical role in IL-4-mediated responses, lacked the decreasedpathology of EAE that was seen in the infected control mice (Sewell et al. 2003).Similar results were noted in mice treated with soluble egg antigen (SEA) fromS. japonicum (Zheng et al. 2008) and in mice infected with Fasciola hepatica(Walsh et al. 2009) and Trichinella spiralis (Gruden-Movsesijan et al. 2008). Studies with MS patients have also been conducted, and a recent one found thathelminth infection, as measured by many indicators of MS disease, was able toalleviate many symptoms of MS in patients; these positive results were associatedwith increased production of Th2-type cytokines IL-10 and TFG-b (Correale andFarez 2007). Additionally, it was found that MS patients with helminth infectionshad induced regulatory B cells, and through the increased production of IL-10 theseB cells blunted the characteristic immune response of MS (Correale et al. 2008).
    • 218 J. Bolstridge et al.On the basis of these findings, Correale and Farez (2007) studied the effects of toll-like receptors (TLRs) on dendritic cell (DC) and B cell regulation in helminth-infected MS patients. TLR2 expression on DC and B cells was required for the SEAmodulation of these cells to an anti-inflammatory profile (Correale and Mauricio2009). These clinical studies, as well as the experimental mice studies, showed thatthe ability of helminths to shift towards a Th2-type immune response could be usedas a future treatment for patients with MS.9.4 Rheumatoid ArthritisRheumatoid Arthritis (RA) is a common autoimmune disease that mainly affectsthe bones, cartilage, and the synovium of patients (Kuijk and Van Die 2010). It isunknown what initiates this disease, but it is thought that autoreactive T cells andautoantibodies play an important role in the sustained inflammatory response(Kuijk and Van Die 2010). There are multiple drug therapies available, but formany patients the drugs never fully alleviate the disease. Animal models have been used in the majority of studies on the effects ofhelminth therapy on RA with the majority of these studies using collagen-inducedarthritis (CIA) as a model for RA. Early studies found that the incidence of arthritisis less severe in rats infected with the pinworm Syphacia oblevata (Pearson andTaylor 1975). Nippostrongylus brasiliensis (a rat nematode) has also been shown toameliorate the severity of CIA in mice (Salinas-Carmona et al. 2009). In a studywhich compared the cytokine production in CIA-administered uninfected andS. mansoni-infected mice, Th1-type (IFN-g) and inflammatory-type (TNF-a andIL-17A) cytokines were significantly lower in infected mice, while Th2-type (IL-4,IL-10) cytokines were upregulated in infected mice (Osada et al. 2009). Further-more, S. mansoni infection prevented the augmentation of IL-1-b, IL-6, and recep-tor activation of NFkB (Osada et al. 2009). These findings show that S. mansoniinfection has anti-inflammatory effects which prevent bone destruction (Osada andKanazawa 2010). In addition to helminth infection, worm products have been usedin various experiments on animals afflicted with CIA. Rocha et al. (2008) used anextract from Ascaris suum (a pig roundworm) to treat mice and rats with zymosan-induced arthritis (ZMA) and CIA. By all measures of clinical severity, A. suumextract functioned species-independently to reduce the severity of the arthritispathology. One of the more promising areas of research of helminth therapy as a treatmentfor arthritis concerns a protein termed ES-62 (Kuijk and Van Die 2010). ES-62 is aprotein originally derived from Ancanthocheilonema viteae (a rodent filarial nema-tode), which contains phosphorylcholine (PC) in its natural form, and is known toinduce general anti-inflammatory Th2-type properties (Harnett et al. 2003).McInnes et al. (2003) studied mice afflicted with CIA, and observed that micethat were subcutaneously administered PC-containing ES-62 had an inhibited
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 219Th1-type inflammatory cytokine (TNF-a, IL-6, and IFN-g) response. In addition tothis, cells derived from human RA donors had suppressed TNF-a and IL-6 produc-tion (McInnes et al. 2003). Harnett et al. (2008) found that these immunosuppres-sive properties of ES-62 are dependent on the PC moiety. The research intohelminth therapy as a treatment for RA, particularly using ES-62, may eventuallylead to an effective treatment for patients suffering from RA.9.5 Type-1 DiabetesType-1 Diabetes (T1D) is a disease caused by the autoimmune destruction ofpancreatic b cells, which produce the hormone insulin. The full mechanism behindthis destruction is unknown, but CD4+ and CD8+ T cells are known to playimportant roles in this autoimmune reaction (Tisch and McDevitt 1996). Thedisease is characterized as a Th1-type response, but studies have been foundwhich implicate Th17 in T1D (Osada and Kanazawa 2010). Though T1D ismanageable, the lifelong symptoms and therapy are difficult for patients, and thismake preventative and regenerative therapies important to the millions of peopleafflicted with this disease (Kuijk and Van Die 2010). The second half of the twentieth century has seen a rise of T1D (Gale 2002).Onkamo et al. (1999) found a 3% per year increase in T1D from 1960 to 1996.Diabetes has a particularly high rate in Western countries, and environmentalfactors, including the decrease in chronic helminth infections, are likely a majorcause of this increase in disease incidence (Gale 2002). Infections with a variety of parasites have been found to have a beneficial effecton induced diabetes in nonobese diabetic (NOD) mice (Table 9.1). Cooke et al.(1999) infected mice with S. mansoni and found a 40% decrease in the incidence ofdiabetes in infected NOD mice. Thirty percent of S. mansoni-infected mice stilldeveloped diabetes, and this could be explained by the length of time it takes for theinfection to produce eggs (Cooke et al. 1999). This study also found that injection ofeggs into the mice completely blocked the incidence of diabetes (Cooke et al.1999). Zaccone et al. (2003) observed that the effects of S. mansoni SEA on NODmice were characterized by a switch from diabetes-associated Th1 to Th2 response,as indicated by IL-4, IL-5, IL-10, and IL-13 production. Zaccone et al. (2009)investigated the protective mechanism of SEA further, and observed that NODmice that were administered SEA had a significant number of pancreatic Treg cellspositive for expression of forkhead box P3 (FoxP3). This protection by FoxP3+Tregs was dependent on TGF-b and DC cells (Zaccone et al. 2009). Studiesconducted with Litomosoides sigmodontis (a mouse filarial worm) have alsofound a shift to a Th2-type response in conjunction with increased incidence ofFoxP3+ Treg cells (H€bner et al. 2009). A possible therapy that targets these uspecific FoxP3+ Tregs would be preferable, because it would allow for the specificsuppression of immune response while allowing response to other antigens
    • 220 J. Bolstridge et al.(Zaccone and Cooke 2010). Multiple molecules have been implicated as possibletriggers for a Treg response that would be beneficial for patients with diabetes(Zaccone and Cooke 2010). Many other helminths have been used in the treatment of NOD mice, includingthe nematodes Dirofilaria immitus (Imai et al. 2001), Heligomosomoides polygyrus(Liu et al. 2009; Saunders et al. 2007), Trichinella spiralis (Saunders et al. 2007),and the cestode Taenia crassiceps (Espinoza-Jimenez et al. 2010). Saunders et al.(2007) studied both H. polygyrus and T. spiralis, and found that these twonematodes had different mechanisms in response to NOD mice; this is probablydue to differences in the life cycles of the two parasites. This is an importantobservation, because the diversity of life stages, and the molecules present inthese life stages, could make a difference in the efficacy of helminth therapy onpatients with T1D. Figures 9.1–9.3 show the life cycles of three different hel-minths, and they illustrate the diversity of the life cycles of different helminths.Helminth therapy could solve the problem of monotonous, life-spanning therapiesthat current patients with T1D must endure, and may be used as a regenerativeor preventative treatment.9.6 Asthma and Allergic ResponsesThe immune system responds to a seemingly infinite amount of harmful foreignantigens while ignoring harmless antigens (Smits et al. 2010). As many of thecurrent world health problems are being treated, many nations, particularly Westernnations, have seen an epidemic rise in childhood allergies, including rhinitis, atopicdermatitis, and allergic and nonallergic asthma (Schaub et al. 2006). The hygienehypothesis has been proposed as a possible environmental factor behind this rise inallergic diseases. The typical allergic response is a result of Th2-promoted immunity (Folkertset al. 2000). This makes it difficult to understand how helminths, which are thoughtto promote a Th2-type environment, can blunt the self-reactive response seen intypical childhood allergy. What has been suggested to date is that helminths work tocreate a regulatory network of Tregs, B cells, DCs, macrophages, and local stromalcells to create an anti-inflammatory environment rich in IL-10 and TGF-b (Smitset al. 2010). Some helminths have been found to use a Treg mechanism to reduce inflamma-tion of allergic responses in mouse models (Table 9.1), including S. japonicum(Yang et al. 2006), H. polygyrus (Wilson et al. 2005), and L. sigmodontis (Dittrichet al. 2008). In summary, the aforementioned studies found a decrease in IL-5 andother Th2 cytokines, as well as a rise in Tregs and IL-10, when mice wereadministered helminths for suppression of sensitization and inflammation in amurine asthma model. It should be noted that Wilson et al. (2005) found that
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 221mice that were deficient in IL-10 still had suppression of asthma by helminthinfection, illustrating that IL-10 is not necessary for this effect. Other mechanisms have been proposed for helminth protection against allergies.Mangan et al. (2004) studied the effects of S. mansoni infection on anaphylaxis inmice, and found that IL-10-producing B cells had a critical role in the protectionthat this helminth provided. Studies have also looked into the effects of variousworm antigens and life-cycle stages on allergic response. Mangan et al. (2006)found that infection with male-only S. mansoni worms blunted allergen-inducedairway hyperresponsiveness in mice, while traditional infection with male andfemale worms exacerbated this harmful immune response. Figure 9.3 shows thelife cycle of S. mansoni. Itami et al. (2005) studied the effects of the allergenicprotein of A. suum (APAS-3) and the suppressive protein of A. suum (PAS-1) onmurine experimental asthma. APAS-3 induced a Th2-type immune response whileexacerbating IgE antibody production, eosinophilic airway inflammation, andhyperresponsiveness (Itami et al. 2005). Mice that were administered PAS-1 hadreduced values comparable to control mice (Itami et al. 2005). Various life cyclestages and worm products can induce different immune responses in experimentalmodels of asthma. T. suis live eggs were used in a study on human patients with grass pollen-induced allergic rhinitis (Bager et al. 2010). No significant differences were foundin mean symptom scores, total histamine, or grass-specific IgE (Bager et al. 2010).It could be that treatment with T. suis does not create an immune-suppressiveenvironment which quells the symptoms of a patient with allergies. Other wormantigens or other helminths should be investigated for their efficacy as a treatmentfor patients with asthma and other allergies.9.7 Concluding RemarksThere has been a global increase in autoimmune diseases, particularly the onesmentioned in this review. With the rise in the incidence of such diseases comesan increased need for novel therapies to treat or ameliorate the pathology of theseillnesses. Helminth therapy is a promising area of research on these diseasesparticularly because of the many successful studies that have been done usinganimal models. The efficacy of helminth therapy to treat autoimmune disordershas been demonstrated unequivocally. What must now be done is to developactual treatments for patients suffering from these diseases. Of most importancein this regard is the development of treatments which do not involve the use oflive worms or viable eggs, thus lowering the risk of infection and further justify-ing use of the treatment. If advances in this field continue, helminth therapy willsomeday become a viable treatment option for patients suffering from autoim-mune disease.
    • 222 J. Bolstridge et al.ReferencesAlic M (2000) Inflammatory bowel diseases are diseases of higher socioeconomic status: dogma or reality? Am J Gastroenterol 95:3332–3333Bager P, Arnved J, Ronborg S, Wohlfahrt J, Poulsen LK, Westergaard T, Petersen HW, Kristensen B, Thamsborg S, Roepstorff A, Kapel C, Melbye M (2010) Trichuris suis ova therapy for allergic rhinitis: a randomized, double-blind, placebo-controlled clinical trial. J Allergy Clin Immunol 125:123–130Braus NA, Elliott DE (2009) Advances in the pathogenesis and treatment of IBD. Clin Immunol 132:1–9Cooke A, Tonks P, Jones FM, O’Shea H, Hutchings P, Fulford AJC, Dunne DW (1999) Infection with Schistosoma mansoni prevents insulin dependent diabetes mellitus in non-obese diabetic mice. Parasite Immunol 21:169–176Correale J, Farez M (2007) Association between parasite infection and immune responses in multiple sclerosis. Ann Neurol 61:97–108Correale J, Mauricio F (2009) Helminth antigens modulate immune responses in cells from multiple sclerosis patients through TLR2-dependent mechanisms. J Immunol 183:5999–6012Correale J, Farez M, Razzite G (2008) Helminth infections associated with multiple sclerosis induce regulatory B cells. Ann Neurol 64:187–199Croese J, O’Neil J, Masson J, Cooke S, Melrose W, Pritchard D, Speare R (2006) A proof of concept study establishing Necator americanus in Crohn’s patients and reservoir donors. Gut 55:136–137Dittrich AM, Erbacher A, Specht S, Diesner F, Krokowski M, Avagyan A, Stock P, Ahrens B, Hoffmann WH, Hoerauf A, Hamelmann E (2008) Helminth infection with Litomosoides sigmodontis induces regulatory T cells and inhibits allergic sensitization, airway inflammation, and hyperreactivity in a murine asthma model. J Immunol 180:1792–1799Ehrhardt RO (1996) New insights into the immunopathology of chronic inflammatory bowel disease. Semin Gastrointest Dis 7:144–150Elliott DE, Li J, Blum A, Metwali A, Qadir K, Urban JF Jr, Weinstock JV (2003) Exposure to schistosome eggs protects mice from TNBS-induced colitis. Am J Physiol 284:385–391Elliott DE, Setiawan T, Metwali A, Blum A, Urban JF Jr, Weinstock JV (2004) Heligmosomoides polygyrus inhibits established colitis in IL-10-deficient mice. Eur J Immunol 34:2690–2698Elliott DE, Summers RW, Weinstock JV (2005) Helminths and the modulation of mucosal inflammation. Curr Opin Gastroenterol 21:51–58Espinoza-Jimenez A, Rivera-Montoya I, Cardenas Arreola R, Moran L, Terrazas LI (2010) Taenia crassiceps infection attenuates multiple low-dose streptozotocin-induced diabetes. J Biomed Biotechnol. doi:10.1155/2010/850541Folkerts G, Walzl G, Openshaw PJM (2000) Do common childhood infections ‘teach’ the immune system not to be allergic? Immunol Today 21:118–120Fukumoto S, Iriko H, Otsuki H (2009) Helminth infections prevent autoimmune diseases through Th2-type immune response. Yonago Acta Med 52:85–104Gale EA (2002) The rise of childhood type 1 diabetes in the 20th century. Diabetes 51:3353–3361Gruden-Movsesijan A, Ilic N, Mostarica Stojkovic M, Stosic-Grujicic S, Milic M, Sofronic- Milosavljevic L (2008) Trichinella spiralis: modulation of experimental autoimmune enceph- alomyelitis in DA rats. Exp Parasitol 118:641–647Harnett W, Harnett MM, Byron O (2003) Structural/functional aspects of ES-62: a secreted immunomodulatory phosphorylcholine-containing filarial nematode glycoprotein. Curr Prot Peptide Sci 4:59Harnett MM, Kean DE, Boitelle A, McGuiness S, Thalhamer T, Steiger CN, Egan C, Al-Riyami L, Alcocer MJ, Houston KM, Gracie JA, McInnes IB, Harnett W (2008) The phosphorycholine moiety of the filarial nematode immunomodulator ES-62 is responsible for its anti-inflamma- tory action in arthritis. Ann Rheum Dis 67:518–523
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 223H€bner MP, Stocker JT, Mitre E (2009) Inhibition of type 1 diabetes in filaria-infected non-obese u diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology 127:512–522Humphreys NE, Xu D, Hepworth MR, Liew FY, Grencis RK (2008) IL-33, a potent inducer of adaptive immunity to intestinal nematodes. J Immunol 180:2443–2449Hunter MM, Wang A, McKay D (2007) Helminth infection enhances disease in a murine TH2 model of colitis. Gastroenterology 132:1320–1330Hunter MM, Wang A, Parhar KS, Johnston MJG, Van Rooijen N, Beck PL, McKay DM (2010) In vitro-derived alternatively activated macrophages reduce colonic inflammation in mice. Gas- troenterology 138:1395–1405Imai S, Tezuka H, Fujita K (2001) A factor of inducing IgE from a filarial parasite prevents insulin-dependent diabetes mellitus in nonobese diabetic mice. Biochem Biophys Res Com- mun 286:1051–1058Itami DM, Oshiro TM, Araujo CA, Perini A, Martins MA, Macedo MS, Macedo-Saores MF (2005) Modulation of murine experimental asthma by Ascaris suum components. Clin Exp Allergy 35:873–879Johnston MJG, Wang A, Catarino MED, Ball L, Phan VC, MacDonald JA, McKay DM (2010) Extracts of the rat tapeworm, Hymenolepis diminuta, suppress macrophage activation in vitro and alleviate chemically induced colitis in mice. Infect Immunol 78:1364–1375Khan WI, Blennerhasset PA, Varghese AK, Chowdhury SK, Omsted P, Deng Y, Collins SM (2002) Intestinal nematode infection ameliorates experimental colitis in mice. Infect Immunol 70:5931–5937Kuijk LM, Van Die I (2010) Worms to the rescue: can worm glycans protect from autoimmune diseases? Life 62:303–312Kurtzke JF (2000) Multiple sclerosis in time and space – geographic clues to cause. J Neurovirol 6: S134–S140La Flamme AC, Ruddenklau K, Backstrom BT (2003) Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyeli- tis. Infect Immunol 71:4996–5004Liu Q, Sundar K, Mishra PK, Mousavi G, Liu ZG, Gaydo A, Alem F, Lagunoff D, Bleich D, Gause WC (2009) Helminth infection can reduce insulitis and type 1 diabetes through CD25- and IL- 10-independent mechanisms. Infect Immunol 77:5347–5358Mangan NE, Fallon RE, Smith P, Van Rooijen N, McKenzie AN, Fallon PG (2004) Helminth infection protects mice from anaphylaxis via IL-10-producing B cells. J Immunol 173:6346–6356Mangan NE, Van Rooijen N, McKenzie ANJ, Fallon PG (2006) Helminth-modified pulmonary immune response protects mice from allergen-induced airway hyperresponsiveness. J Immu- nol 176:138–147McFarland HF, Martin R (2007) Multiple sclerosis: a complicated picture of autoimmunity. Nat Immunol 8:913–919McInnes IB, Leung BP, Harnett M, Gracie JA, Liew FY, Harnett W (2003) A novel therapeutic approach targeting articular inflammation using the filarial nematode-derived phosphorylcho- line-containing glycoprotein ES-62. J Immunol 171:2127–2133Mo HM, Liu WQ, Lei JH, Cheng YL, Wang CZ, Li YL (2007) Schistosoma japonicum eggs modulate the activity of CD4+ CD25+ Tregs and prevent development of colitis in mice. Exp Parasitol 116:385–389Moreels TG, Nieuwendijk RJ, De Man JG, De Winter BY, Herman AG, Van Marck EA, Pelck- mans PA (2004) Concurrent infection with Schistosoma mansoni attenuates inflammation induced changes in colonic morphology, cytokine levels, and smooth muscle contractility of trinitrobenzene sulphonic acid induced colitis in rats. Gut 53:99–107Motomura Y, Wang H, Deng Y, El-Sharkawy RT, Verdu EF, Khan WI (2009) Helminth antigen- based strategy to ameliorate inflammation in an experimental model of colitis. Clin Exp Immunol 155:88–95
    • 224 J. Bolstridge et al.Onkamo P, Vaananen S, Karvonen M, Tuomilehto J (1999) Worldwide increase in incidence of type 1 diabetes – the analysis of the data on published incidence trends. Diabetologia 42:1395–1403Osada Y, Kanazawa T (2010) Parasitic helminths: new weapons against immunological disorders. J Biomed Biotechnol. doi:10.1155/2010/743758Osada Y, Shimizu S, Kumagai T, Yamada S, Kanazawa T (2009) Schisosoma mansoni infection reduces severity of collagen-induced arthritis via down-regulation of proinflammatory media- tors. Int J Parasitol 39:457–464Pearson DJ, Taylor G (1975) The influence of the nematode Syphacia oblevata on adjuvant arthritis in the rat. Immunology 29:391–396Reddy A, Fried B (2007) The use of Trichuris suis and other helminth therapies to treat Crohn’s disease. Parasitol Res 100:921–927Reddy A, Fried B (2009) An update on the use of helminths to treat Crohn’s and other autoimmune diseases. Parasitol Res 104:217–221Rocha FAC, Leite AKRM, Pompeu MML, Cunha TM, Verri WA, Soares FM, Castro RR, Cunha FQ (2008) Protective effect of an extract from Ascaris suum in experimental arthritis models. Infect Immunol 76:2736–2745Ruyssers NE, De Winter BY, De Man JG, Loukas A, Pearson MS, Weinstock JV, Van den Bossche RM, Martinet W, Pelckmans PA, Moreels TG (2009) Therapeutic potential of helminth soluble proteins in TNBS-induced colitis in mice. Inflamm Bowel Dis 15:491–500Ruyssers NE, De Winter BY, De Man JG, Ruyssers ND, Van Gils AJ, Loukas A, Pearson MS, Weinstock JV, Pelckmans PA, Moreels TG (2010) Schistosoma mansoni proteins attenuate gastrointestinal motility disturbances during experimental colitis in mice. World J Gastroentrol 16:703–712Salinas-Carmona MC, De la Cruz-Galacia G, Perez-Rivera I, Solis-Soto JM, Segoviano-Ramirez JC, Vazquez AV, Garza MA (2009) Spontaneous arthritis in MRL/lpr mice is aggravated by Staphylococcus aureus and ameliorated by Nippostrongylus brasiliensis infections. Autoim- munity 42:25–32Sartor RB (2006) Mechanisms of disease: pathogenesis of Crohn’s disease and ulcerative colitis. Nat Clin Prac Gastroenterol Hepatol 3:390–407Saunders KA, Raine T, Cooke A, Lawrence CE (2007) Inhibition of autoimmune type 1 diabetes by gastrointestinal helminth infection. Infect Immunol 75:397–407Schaub B, Lauener R, von Mutius E (2006) The many faces of the hygiene hypothesis. J Allergy Clin Immunol 117:969–977Sewell D, Qing Z, Reinke E, Elliot D, Weinstock J, Sandor M, Fabry Z (2003) Immunomodulation of experimental autoimmune encephalomyelitis by helminth ova immunization. Int Immunol 15:59–69Smith P, Mangan NE, Walsh CM, Fallon RE, McKenzie AN, Van Rooijen N, Fallon PG (2007) Infection with a helminth parasite prevents experimental colitis via a macrophage-mediated mechanism. J Immunol 178:4557–4566Smits HH, Everts B, Hartgers FC, Yazdanbakhsh M (2010) Chronic Helminth infections protect against allergic diseases by active regulatory processes. Curr Allergy Asthma Rep 10:3–12Summers RW, Elliott DE, Urban JF Jr, Thompson R, Weinstock JV (2005a) Trichuris suis therapy in Crohn’s disease. Gut 54:87–90Summers RW, Elliott DE, Weinstock JV (2005b) Is there a role for helminths in the therapy of inflammatory bowel disease? Nat Clin Prac Gastroenterol Hepatol 2:62–63Summers RW, Elliott DE, Weinstock JB (2005c) Why Trichuris suis should prove safe for use in inflammatory bowel diseases. Inflamm Bowel Dis 11:783–784Summers RW, Elliott DE, Urban JF Jr, Thompson RA, Weinstock JV (2006) Trichuris suis therapy for active ulcerative colitis: a randomized controlled trial. Gastroenterology 128:825–832Tisch R, McDevitt H (1996) Insulin-dependent diabetes mellitus. Cell 85:291–297
    • 9 Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases 225Van Kruiningen HJ, West AB (2005) Potential danger in the medical use of Trichuris suis for the treatment of inflammatory disease. Inflamm Bowel Dis 11:515Walsh KP, Brady MT, Finlay CM, Boon L, Mills KH (2009) Infection with a helminth parasite attenuates autoimmunity through TGF-b-mediated suppression of Th17 and Th1 responses. J Immunol 183:1577–1586Weinstock JV, Summers RW, Elliott DE (2005) Role of helminths in regulating mucosal inflam- mation. Springer Semin Immunopathol 27:249–271Wilson MS, Taylor MD, Balic A, Finney CAM, Lamb JR, Maizels RM (2005) Suppression of allergic airway inflammation by helminth-induced regulatory T cells. J Exp Med 202:1199–1212Yang JH, Zhao JQ, Yang YF, Zhang L, Yang X, Zhu X, Ji MJ, Sun NX, Su C (2006) Schistosoma japonicum egg antigens stimulate CD4+CD25+ T cells and modulate airway inflammation in a murine model of asthma. Immunology 120:8–18Yoshimoto T, Nakanishi K (2006) Roles of IL-18 in basophils and mast cells. Allergol Int 55:105–113Zaccone P, Cooke A (2010) Harnessing CD8+ regulatory T cells: therapy for type-1 diabetes? Immunity 32:504–506Zaccone P, Fehervari Z, Jones FM, Sidobre S, Kronenberg M, Dunne DW, Cooke A (2003) Schistosoma mansoni antigens modulate the activity of the innate immune response and prevent onset of type 1 diabetes. Eur J Immunol 33:1439–1449Zaccone P, Burton O, Miller N, Jones FW, Dunne DW, Cooke A (2009) Schistosoma mansoni egg antigens induce Treg that participate in diabetes prevention in NOD mice. Eur J Immunol 39:1098–1107Zheng X, Hu X, Zhou G, Lu Z, Qiu W, Bao J, Dai Y (2008) Soluble egg antigen from Schistosoma japonicum modulates the progression of chronic progressive experimental autoimmune encephalomyelitis via Th2-shift response. J Neuroimmunol 194:107–114