Unraveling the Hygiene Hypothesis of helminthes and autoimmunity: origins, pathophysiology, and clinical applications

The ability of infectious agents to modulate the immune system has long been a fascinating topic. For almost half a century, infections have been widely demonstrated to act as triggering factors of autoimmune response. Viral agents, such as Epstein-Barr virus, cytomegalovirus, and parvovirus B19, as well as numerous bacteria and parasites have been associated with the presence of a wide variety of autoantibodies and found to contribute to the pathogenesis of autoimmune diseases [14,21]. Thus, parasitic infections have been shown to promote autoimmunity through various mechanisms, including molecular mimicry of parasitic epitopes, alteration of host antigens, polyclonal activation, and expansion of autoreactive B-cell clones, as well as manipulation of the idiotypic network [22].

At the same time, it became increasingly evident that infectious microorganisms could also exert an immunomodulatory and immunodepressant action on the immune system, resulting in a protective effect against immune-mediated conditions such as allergies and autoimmune diseases. The changes that have accompanied the recent modernization in Western countries, such as migration from rural to urban areas, improved sanitation, access to clean water, control of food production, or even vaccination campaigns, have reduced contact with these ancestral microorganisms with which mammals had coexisted and co-evolved for millennia [23]. Hence, the HH concept emerged, postulating that the slightest exposure to these immunoregulatory infectious agents – called ‘Old Friends’ by Rook [24] – in industrialized countries due to improvement in hygiene conditions promotes the development of chronic inflammatory disorders and contributes to their recent rise [15].

This theory was first suggested by Greenwood [25], nearly half a century ago, when reporting a lower prevalence of autoimmune diseases in Nigerians. He suggested an immunomodulatory effect of multiple parasitic infections since childhood, later confirmed by demonstrating that infection of different strains of mice prone to developing autoimmune diseases with the rodent malaria parasite Plasmodium berghei prevented the occurrence of the disease [26]. The inverse correlation between the dramatic decrease in infections in industrialized countries due to better hygiene and the concomitant increase in immune-mediated diseases was finally clarified by Strachan in 1989 [16]. Indeed, by following a cohort of more than 17,000 children born in 1958 for 23 years, he observed an inverse relationship between the number of older siblings in the household and the prevalence of hay fever, therefore concluding that allergies could be prevented by infections in early childhood. According to Strachan, a lower exposure to these infections might promote atopic diseases. These observations have led to the birth of a new paradigm on the role of infectious agents in immune disorders. Since then, the HH has been widely powered by epidemiological, experimental, and clinical data.

The HH, as formulated by Strachan a quarter-century ago [16], originally focused on allergic diseases. It claimed that their recent rise in Western countries was promoted by reduced exposure to microorganisms due to improved hygiene conditions. Since these early observations, many epidemiological data have reinforced this theory, first on allergic disorders and then extending to autoimmune diseases.

A number of studies have investigated the prevalence of allergic diseases according to living conditions. First, the initial observation of Strachan [16], demonstrating an inverse correlation between the sibship size and the subsequent risk of allergy, has since been widely replicated in a large number of studies in affluent countries [27-30]. Moreover, Strachan et al. [31] recently confirmed, in a broad international study involving more than 500,000 children in 52 countries, the inverse association between the risk of developing hay fever or eczema and the total number of siblings; the association being stronger in more affluent countries. Otherwise, pet ownership has also been linked to a decreased prevalence of allergic diseases. In a recent meta-analysis including 36 publications, Pelucchi et al. [32] reported a favorable effect of exposure to pets, especially to dogs, on the risk of atopic dermatitis in infants or children. Similarly, worst living standards in Eastern Germany compared with Western Germany were associated with a reduced occurrence of atopic diseases [33]. Thereafter, the prevalence of atopy experienced an increase in children in Eastern Germany born after the reunification of Germany in 1990 [34]. Equally, other lifestyle factors, including low antibiotic consumption [35,36] and growing up in rural areas, were associated with a diminished prevalence of allergic diseases [37,38]. In developing countries, an inverse relationship was also observed between the prevalence of parasitic infections, especially helminthic, and the risk of allergic diseases. For example, in Ecuador [39], Gabon [40], and Brazil [41], helminth infections were shown to have a protective effect on allergic reactivity. Conversely, anti-helminthic treatment of chronically infected children in Gabon [40], Venezuela [42], and Vietnam [43] resulted in increased atopic reactivity.

The HH was later extended when the protective effect of infectious agents, especially parasites, against autoimmune diseases was suggested through various epidemiological studies [15]. As previously reported, the number of siblings has been shown to correlate inversely to the risk of MS [44,45]. Furthermore, in the Italian island of Sardinia, several epidemiological and immunogenetic evidences [46-49] link malaria eradication 50 years ago with the concomitant increase of MS. It is assumed that the strong genetic selective pressure of malaria along the centuries led to the selection of polymorphisms and genotypes conferring resistance to Plasmodium falciparum, the causative agent of malaria. These polymorphisms are responsible for the increased immune reactivity required to control malaria. As soon as the immunoregulatory organism was withdrawn from the environment by the modern lifestyle, these genetic variants led to excessive inflammation and became susceptibility factors for chronic inflammatory disorders, especially MS.

The Karelia region is also of great interest to investigate the influence of lifestyle and infections on the risk of immune-mediated disorders. This region is divided into a Finnish area, characterized by high standards of hygiene, and a Russian area, with poorer hygiene and an increased rate of infections. Finnish Karelian maintain one of the highest prevalence of autoimmune and allergic diseases, while Russian Karelian prevalence is far lower, despite sharing the same genetic background. For example, the incidence of T1D is six-fold higher in Finland compared to the adjacent Karelian republic of Russia, the wide gap in infection rates between the two regions being strongly suspected to contribute to this difference [50,51]. Subsequently, Weinstock et al. [52] expanded the HH to IBD based on the increasing prevalence of IBD in the US contrasting with the declining prevalence of helminthes. This observation has since been confirmed in other parts of the world. In sub-Saharan Africa, where helminthic infestation is frequent, a low incidence and prevalence of IBD is observed which cannot be explained by genetic factors due to the fact that, in black populations of the US and UK, the incidence of IBD is approaching that of the white populations [53]. Moreover, migration studies have shown that descendants of immigrants coming from a country with a low incidence acquire the same incidence as the host country, as illustrated for T1D [54,55] and MS [56,57]. Similarly, the prevalence of systemic lupus erythematosus (SLE) was found to be much higher in African Americans compared to West Africans [58]. Interestingly, a case–control study in India showed that none of the patients with rheumatoid arthritis (RA) were positive for circulating filarial antigen in contrast to 40% of healthy controls [59].

Such epidemiological observations raise questions concerning the nature of the protective infectious agents involved and the mechanisms through which they modulate the immune system and thus the risk of inflammatory disorders.

These epidemiological data, in conjunction with other data, reinforced the paradigm that infectious agents may confer a protective effect against chronic inflammatory diseases. Therefore, it is of interest to unravel and clarify the mechanisms of this theory.

It is of interest to attempt to understand what developments in our lifestyle have led to the dramatic changes in our contact with these ancestral organisms within a few decades.

First, urbanization and migration of populations to cities, as well as public health measures, such as control of food production, water quality, and advances in sanitation and health care, have significantly reduced or almost eradicated some infections in Western countries, particularly helminthic infections [65,66], malaria, mycobacterial infections [67], and hepatitis A. As indicated above, epidemiological data have inversely correlated the eradication of some of these infections, especially helminthic infections and malaria, with an increase in the prevalence of immune-mediated diseases in Western countries.

Otherwise, the composition of our gut microbiota strongly depends on our environment, mainly on our microbial contacts as well as many other factors that can modulate it. It has been demonstrated that the gut microbiota plays a critical role in regulating the immune response [68,69]. Thus, any factor causing a dysregulation of the microbiota can affect the balance of our immune system and thereby promote the development of chronic inflammatory diseases [70-72]. Hence, population migration from rural areas in contact with animals and environmental flora to more sanitized urban areas has affected the microbiota diversity [73,74], thereby likely favoring immune-mediated disorders. Interestingly, several studies [17,75,76] have suggested that the protective effect of large families or owning animals on atopic diseases reported in epidemiological studies could be partially related to an increase in gut microbiota diversity and richness. This may explain the pioneering observations reported by Strachan [16] on the protective effect of a large number of siblings on the occurrence of allergic disorders. Similarly, a Western diet [77-80], widespread use of antibiotics [81], and birth by caesarean section [82] are well-established factors disrupting intestinal microbiota. Several studies have demonstrated that exposure to antibiotics at an early age may cause dysbiosis, increasing the risk of subsequent allergic disorders [36,83,84]. In addition, caesarean birth has been associated with a higher risk of asthma [85], T1D [86], MS [87], and celiac disease [88,89].

Thus, eradication of most of these ‘Old Friends’ from our environment may have contributed to the recent outbreak in inflammatory disorders in Western countries. To better explain this inverse correlation, it is important to unravel the wide immunomodulatory effects of these microorganisms on their host’s immune system. To date, helminthes have provided the greatest information to specify the protective mechanisms developed in the host, most data being derived from animal models.

Helminthes are eukaryotic parasitic worms. In 2008, it was estimated that about 37% of the world’s population was infected with helminthes, mainly in developing countries, helminthiasis now being rare in industrialized countries [66]. Helminthes’ classification is based on numerous factors, including the external and internal morphology of egg, larval, and adult stages. These parasites are divided into two phyla: Platyhelminthes (flatworms), including both trematodes (flukes) and cestodes (tapeworms), and Nemathelminthes, including only one class, namely nematodes (roundworms) [90]. Helminthes most frequently live in the gastrointestinal tract of their host, but may also colonize other organs. It is worth noting that helminthes have co-evolved with their host for millennia; their goal is not to kill their host but to survive as long as possible by creating a state of tolerance. To achieve this, helminthes are able, through various mechanisms, to finely modulate the host immune system to prevent an activation that may lead to their elimination, while not causing too deep an immunosuppression which would cause the host to die from infection. This immunomodulation, by avoiding an excessive activation of the immune system, contributes to host protection against inflammatory disorders.

Numerous studies in animal models have highlighted the intricate mechanisms by which helminthes hamper the host’s immune response. This includes promotion of T-helper-2 (Th2) and inhibition of Th1/Th17 differentiation, amplification of T-regulatory (Treg) and B-regulatory (Breg) cells and type 2-macrophages, orientation of dendritic cells (DCs) towards a tolerogenic phenotype, downregulation of type-2 innate lymphoid cells (ILC2), and modulation of the gut microbiota [24,91-95]. Helminthes’ immunoregulatory effects are illustrated in Figure 1.

The recognition of the extensive immunoregulatory properties of numerous microorganisms from our environment, especially helminthes, initially suggested in the HH and since then widely demonstrated, led, in the 1990s, to their therapeutic application in experimental models and clinical studies of several immune-mediated conditions, including IBD, MS, RA, T1D, celiac disease, Grave’s disease, and psoriasis. Various species of helminthes and different approaches were evaluated, including colonization by helminthes larvae, oral administration of helminthes ova, and the use of helminth-derived antigens. Helminth-derived therapies, as detailed below, were found to both prevent or delay the onset and reduce the severity of autoimmune diseases in both animal models and clinical trials. These experiments are summarized in Table 1.

Strong experimental data using helminthes in various murine models of colitis have suggested the benefit of helminth therapy in IBD [122,123,135,141-148]. Thus S. mansoni soluble egg antigen (SEA) [142] or cercariae [143,145] exposure were shown to significantly attenuate trinitrobenzene sulfonic acid (TNBS)-induced [142,143] or DSS-induced [145] colitis in mice by enhancing IL-4 and IL-10 expression, decreasing INF-γ levels [142,143], or through induction of F4/80+ macrophages [145]. Infection of mice with either T. spiralis cercariae [141] or antigens [147] prior to dinitrobenzene sulfonic acid (DNBS)-colitis induction reduced its severity and was correlated with higher IL-4, IL-13, and TGF-β production and down-regulation of IFN-γ, IL-1β, myeloperoxidase activity, and inducible nitric oxide synthase expression. Similarly, H polygyrus [122,123], Hymenoleptis diminuta (H. diminuta) [144], Schistosoma japonicum (S. japonicum) [146], and C. sinensis [135] were found to attenuate or prevent the Rag IL-10−/− T-cell transfer model of colitis and DNBS-, TNBS-, and DSS-induced colitis, respectively, through mechanisms including promotion of Treg cells, Th2-cytokines (IL-4, IL-5, IL-10), tolerogenic DCs, and M2-macrophages, as well as inhibition of IFN-γ and IL-17 secretion.

These encouraging results have led to several clinical trials [149-152] evaluating the safety and therapeutic potential of helminth therapy, mainly Trichuris suis (T. suis) ova (TSO) in IBD patients. T. suis is a pig whipworm able to colonize a human host only for a short period of time. Following an initial study [149] suggesting that TSO given orally could be a safe and effective treatment of IBD, Summers et al. conducted two trials; an open-label study in 29 patients suffering from active CD as defined by a Crohn’s disease activity index (CDAI) ≥220 [150], and a randomized double blind placebo-controlled trial in 54 patients with active UC, defined by an ulcerative disease activity index (UCDAI) ≥4 [151]. All CD patients ingested 2,500 TSO every 3 weeks for 24 weeks; UC received either 2,500 TSO or placebo orally at 2-week intervals for 12 weeks. At the studies’ conclusion, 79.3% of CD patients responded (decrease in CDAI >100 points or CDAI <150) and 72.4% remitted (CDAI <150), whereas, although UC remission rates between the two groups were not significantly different, improvement of the UCDAI occurred in 43.3% of patients with ova treatment compared with 16.7% given placebo. No side effects were reported in either study. Although T. suis immunoregulatory mechanisms were not studied in these trials, it is assumed that this involves the modulation of Th1, Th2, Treg, and Th17 subsets as suggested in murine models. In October 2013, the TRUST-I phase 2 clinical trial [153] evaluating TSO treatment (7,500 ova every 2 weeks for 12 weeks) versus placebo in 250 moderate-to-severe CD patients failed to reach its primary (100-point CDAI decrease) and key secondary (achieving CDAI <150) endpoints. Despite these discouraging results, the authors assumed, according to subgroup analyses, that the effectiveness of TSO could be higher in severe patients (CDAI >290). A number of clinical trials using TSO in IBD patients have been performed (listed in [95,154]), and the human hookworm Necator americanus (N. americanus) has been suggested as an alternative to T. suis since it is easier to use due to longer-lasting effects [155] and appears to be well tolerated [156].

Many studies [104,106,121,129,157-163] conducted in EAE mice, the main animal model of MS, have highlighted the interest of helminth-derived therapies in this disease. Indeed, prior treatment of mice before EAE induction with either S. mansoni ova [160], cercariae [158], or antigen [162] significantly reduced the incidence as well as the severity of EAE as measured by clinical scores and central nervous system (CNS) inflammation. This protective effect was associated with decreased IL-12, IFN-γ, and TNF-α secretion and higher IL-4, IL-10, and TGF-β levels in periphery. It is of interest to note that increased IL-4-secreting neuroantigen-specific T-cells and reduced macrophage and CD4+ T-cell infiltration were observed in the CNS of infected mice as compared to controls. Similarly, pretreatment of EAE Dark Agouti rats with T. spiralis ES products (ES-L1) [104,163] ameliorated the clinical and histological severity of induced EAE in a dose-dependent manner. The mechanisms involved an inhibition of Th1 and Th17 cytokines (IFN-γ, IL-17) and a promotion of Th2 cytokines (IL-4, IL-10) and TGF-β, as well as induction of Treg cells. Transfer of splenic T-cells from T. spiralis-infected rats into EAE rats led to protection from disease development in some cases. As indicated above, injection of DCs stimulated with T. spiralis ES-L1 products 7 days before EAE induction [121] was also found to ameliorate EAE by increasing IL-4, IL-10, TGF-β, and Treg levels and decreasing IFN-γ and IL-17 secretion, both at the systemic level and in target organs. Further, several studies have demonstrated the benefit of H. polygyrus [129], Trichinella pseudospiralis [106], S. japonicum [164], Fasciola hepatica [161], and Taenia crassiceps [159] infections in preventing or delaying the onset of EAE and improving its severity. These effects result from inhibition of Th1- and Th17-responses with lower IFN-γ, TNF-α, IL-6, and IL-17 secretion, reduction of CNS inflammatory infiltrates, enhanced Th2 cytokine production (IL-4, IL-10), and proliferation of Breg, Treg, M2-macrophage, and tolerogenic DC populations.

To date, few studies have evaluated the therapeutic potential of helminthes in MS patients. The most noteworthy observations were reported by Correale et al. [131,165,166] through several prospective studies comparing a series of 12 patients with MS naturally infected with different species of helminthes (Hymenoleptis nanan, Trichuris trichura, Ascaris lumbricoides, Strongyloides stercolaris, and Enterobius vermicularis) with 12 non-infected MS patients as well as with infected patients without MS and healthy subjects. The authors assessed the clinical, radiological, and immunological characteristics of each group of patients with a 4.6-year follow-up extended to 7.5 years in a later report. During the initial 4.6-year follow-up period [165], parasite-infected MS patients showed a significantly lower number of relapses, reduced disability scores, and lower magnetic resonance imaging activity compared to uninfected MS subjects. Infected patients showed higher IL-10- and TGF-β- and lower IL-12- and IFN-γ-secreting cell levels. Moreover, Treg and IL-10-secreting Breg cells were significantly increased in parasite-infected patients compared to other groups [131]. Interestingly, these Breg cells were also found to produce greater amounts of brain-derived neurotrophic factor and nerve growth factor, raising the possibility that these cells may exert a neuroprotective effect on the CNS [131]. Anti-helminthic treatment of 4 of the 12 patients treated due to gastrointestinal symptoms [166] led to a significant rise in clinical and radiological MS activities and in the number of IFN-γ- and IL-12-secreting cells together with a fall in the levels of Treg cells and TGF-β- and IL-10-secreting cells, which became evident 3 months after anti-helminthic treatment began.

A safety phase 1 study (phase 1 Helminthes-induced Immunomodulatory Therapy – HINT-1) [167] inoculating 2,500 TSO orally every 2 weeks for 3 months in five relapsing-remitting MS patients reported mild gastrointestinal side effects. The mean number of new MRIlesions fell from 6.6 at baseline to 2.0 after 3 months of TSO administration and rose again to 5.8 at 2 months after the end of the study. In view of these encouraging results, several clinical trials are already underway or planned, including an extension of HINT-1 as well as numerous studies evaluating TSO or dermally-administrated hookworm N. americanus as therapies in MS patients (listed in [95,154,168]).

Several helminthic products with immunomodulatory properties have been studied in mice models of RA, the filarial-derived glycoprotein ES-62 being the best characterized [169]. However, so far, no helminth-derived molecules have been used in RA clinical trials.

ES-62 is a tetrameric phosphorylcholine (PC)-containing glycoprotein secreted by the rodent filarial nematode A. vitae first described in 1989 [170]. A decade ago, this glycoprotein was demonstrated to significantly reduce the initiation, severity, and progression of CIA in DBA/1 mice, a murine model of RA [114]. Since then, its protective mechanisms in CIA mice have been elucidated by Harnett et al. through several experiments [108,128,171-173]. ES-62 inhibits Th1- and Th17-responses resulting in decreased levels of IFN-γ, TNF-α, IL-6, and IL-17 both in draining lymph nodes and joints of CIA animals. Regarding Th-17 response, ES-62 down-regulates IL-17 secretion by both innate (γδ T cells) and adaptive (Th17 CD4+ cells) cells via DC-dependent and independent mechanisms [108]. It decreases collagen-specific IgG2a antibody production and reduces effector B-cells, particularly plasma cell activation, proliferation, and joint infiltration. Conversely, ES-62 was found to up-regulate IL-10 secretion by splenocytes and to restore IL-10-secreting Breg cell levels in CIA mice [128]. IL-22 plays a dual role in CIA, being pathogenic during the initiation phase while acting to resolve inflammation and joint damage during established disease. Exposure to ES-62 in vivo suppressed the early peak of IL-22 but induced strong expression at later time points, serum levels of IL-22 correlating inversely with articular scores [172]. Finally, ES-62 is also able to modulate DCs to promote a Th2 response. Interestingly, most of the anti-inflammatory actions of ES-62 in CIA have been shown to be related to its PC moiety [171]. Indeed, the whole ES-62 molecule and a PC-ovalbumin conjugate successfully reduced disease severity by suppressing Th1 cytokine production while a PC-free recombinant form of ES-62 failed to prevent CIA progression [173]. Furthermore, a sulfone-containing PC analogue (11a) was designed and demonstrated to be effective in protecting DBA/1 mice from developing CIA [173]. Apart from A. vitae secretory product, several helminthes, including S. mansoni [107], H. diminuta [174], F. hepatica [175], S. japonicum [176], H. polygyrus, and Nippostrongylus brasiliensis [177], have been demonstrated to effectively prevent RA-like disease in mice models through inhibition of Th1/Th17 cytokine secretion, induction of tolerogenic DCs, and promotion of Treg cell proliferation.

No clinical trial using helminth-derived therapies has so far been conducted in T1D patients. However, a large body of experimental data from non-obese diabetic (NOD) mice [109-113,115,178-181], the murine model of T1D, suggest their effectiveness, especially for S. mansoni [111-113,178,179].

Cooke et al. [178] were the first to suggest S. mansoni infection as a preventive treatment in NOD mice. Infection with S. mansoni cercariae or SEA significantly reduced the spontaneous incidence of diabetes and prevented the class switch from IgM to IgG anti-insulin autoantibodies normally seen in most NOD mice as they approach overt diabetes. The authors subsequently reproduced this protective effect in a series of experiments by specifying its mechanisms [111-113,179]. S. mansoni SEA completely prevented the occurrence of T1D when injected to 4-week-old NOD mice [111] by expanding Treg cells in a TGF-β-dependent manner and Th2 cells with increased secretion of IL-4, IL-5, IL-10, and IL-13. Moreover, T-cells from SEA-treated mice exhibited a reduced ability to transfer diabetes to NOD-severe combined immunodeficiency recipients. NOD mice are known to have deficiency in V alpha 14i NKT cells, the expansion of this population preventing diabetes onset [182]. S. mansoni SEA increased the number of V alpha 14i NKT cells and induced functional changes in DCs, found to secrete more IL-10 and less IL-12. Recently, ω-1, one of the two major glycoproteins secreted by S. mansoni ova, was demonstrated to be responsible for its effects [113]. Several studies also evidenced the efficacy of H. polygyrus [109,180], T. spiralis [109], L. sigmodontis [110,115], and Dirofilaria immitis (D. immitis) recombinant antigen [181] to completely prevent the occurrence of diabetes in NOD mice especially by eliciting a Th2-type response and promoting the proliferation of Treg cells, thereby markedly inhibiting pancreatic insulitis.

Experimental and clinical data evaluating helminth therapy in other inflammatory conditions are scarce.

Regarding celiac disease, a double-blinded placebo-controlled study [183] explored the effects of N. americanus cutaneous inoculations in 10 patients compared with 10 non-infected patients. Inoculations of 15 third-stage larvae were performed at weeks 0 and 12, and a 5-day oral gluten challenge was undertaken at week 20. No significant reduction in symptom severity was seen in infected subjects compared to non-infected patients. However, immunological data from the clinical trial analyzed in a subsequent study [184] found that basal Th1- and Th17-responses were inhibited in the duodenum of hookworm-infected patients with decreased IFN-γ and IL-17A secretion. The authors hypothesized that the infective dose of hookworms used in the trial may be insufficient to effectively suppress the immunopathology of celiac disease.

In SLE, a recent study [185] analyzed, for the first time, the effects of infection of MRL/lpr lupus mice with the trematode S. mansoni. The infection completely changed the phenotype of glomerulonephritis in MRL/lpr mice, switching from a severe diffuse proliferative Th1-mediated pattern towards a membranous Th2-mediated nephritis associated with a better prognosis. This effect was associated with a modulation of the cytokine profile shifting from a Th1 to a Th2 polarization with increased rates of IL-4, IL-5, IL-10, and TGF-β.

In Grave’s disease, prophylactic use of S. mansoni product homogenates in a mouse model prior to disease induction prevented its development through Th2 polarization [186]. This was associated with decreased IgG2a subclass anti-thyroid stimulating hormone receptor antibody production, lower IFN-γ levels, and enhanced Treg proliferation.

Finally, one experiment [187] conducted on the fsn/fsn mouse model of psoriasis demonstrated the efficacy of subcutaneous S. mansoni LNFPIII glycan treatment to prevent the appearance of psoriatic skin lesions as compared with control mice. Skin cells from LNFPIII-treated mice secreted lower amounts of IFN-γ and increased levels of IL-13, evidencing a shift toward a Th2-type response. It is noted that several psoriasis clinical trials using TSO are planned [95,154].

The emerging potential of helminth-derived therapy in autoimmune diseases is raising growing interest. The encouraging data from mouse models and early clinical studies have led to an increase in the number of phase 1 and 2 clinical trial projects in IBD, MS, RA, psoriasis, and celiac disease [154]. Recently, we have successfully employed helminthes’ PC derivatives to treat colitis using a prophylactic protocol in mice [188]. Nevertheless, the field of inflammatory Th1/Th17-mediated diseases that may benefit from such treatment is wide and studies of helminth-derived therapy have only just commenced. Much work remains to be done, including analyzing and extracting the molecules responsible for helminth regulating properties, clarifying their action on the immune system, confirming previous findings in larger prospective trials, and identifying other diseases eligible for this new type of immunomodulation. Furthermore, these immunotherapies require the greatest caution, especially regarding the unclear long-term effects of helminth immunomodulation. The manipulation of the immune response could lead to compromise in the defense mechanisms against other pathogens or cancers. The possibility of parasites inducing chronic infection, which may be less controllable, also needs to be considered. Therefore, the use of helminth-derived molecules appears to be a more attractive and safe solution [95,154]. If handled cautiously, helminthes might become part of our future therapeutic armamentarium.