For as long as modern humans have existed, they have carried parasitic worms. There are two groups of worms that inhabit the interior of humans: the nematodes (roundworms) and the platyhelminths (flatworms). They have distinct evolutionary histories and whereas some reside harmlessly in the gut others can cause problems. Most of these worms, however, fail to sustain human colonization, presumably because of genetic differences in the human host, and have no association with human illness (e.g., Trichuris suis). |
Helminths have preferences for living in various locations of their host like the intestinal lumen, bile ducts, blood stream, lungs, and elsewhere. In order to accomplish this, they must evade and control the host’s immune system. This has been achieved through millions of years of coevolution allowing time for both the parasite and its host to gradually adjust to this relationship. |
Many worms seem invincible to human defense. Some worms produce factors and receptors with homology to molecules of the human immune system as revealed by recently decoded worm genomes, for example schistosomula can acquire surface molecules from the host, including blood group determinants and MHC molecules, or they can produce cytokine mimics. It is likely that helminths sense hostile changes in the local host environment and take action to quell these responses. Many worms also have a peculiar outer integument that can absorb host molecules and which may assist in cloaking the parasitic organism from host detection. |
Since the death of the host causes the death of the worm, a 'good' parasite, in order to survive, is an organism which imparts some advantage to its host. Clearly, after thousands of years of co-evolution, the human immune system has evolved to handle the presence of most parasitic worms, which have, in turn, developed adaptations that enable them to live for years in a human host. |
The cloning of the genomes of some helminths has allowed a systematic search for substances with potential immunomodulatory activity. Analysis of the Trichuris suis’ transcriptome has led to the identification of more than a hundred proteins containing conserved domains or signatures relevant to inflammation and immunity, like proteases, protease inhibitors, kinases and other proteins. Whether these proteins are synthesized and what their activities are remain to be investigated.These molecules seem to have three major effects on the immune system (Autoimmunity: The worm returns, 2012). |
First, they seem to cause changes that activate regulatory T cells such as Treg. These cells dampen immune responses and curb autoimmunity — by, for example, increasing the production of regulatory molecules such as interleukin-10 (IL-10) and Transforming Growth Factor-β (TGF-β). |
Second, helminths seem to act on other cells, like regulatory dendritic cells and macrophages. These prevent the activation of dangerous effector T cells, which normally lead to inflammation and disease. |
Both of these effects seem to protect from autoimmunity in a redundant fashion. This redundancy may be one of the reasons why helminths are so effective in controlling these immune-mediated diseases. |
Third, worms seem to alter the bacterial composition of intestinal flora. Research in mice suggests that helminths promote the growth of gut microorganisms typically considered to be 'probiotic', which help to maintain intestinal health. |
Infections with helminth parasites generally induce a strong polarization towards a Th2 type response, leading to the hallmark features of high Th2 cytokine production, eosinophilia, mastocytosis, goblet cell hyperplasia and high levels of IgE antibodies. Despite the successful generation of the Th2 response, worms are often able to survive in the host for long periods of time, causing chronic infections. This long-term survival within an immunocompetent host is facilitated by the induction of immunoregulatory mechanisms, including regulatory T cells (T reg), capable of secreting immunosuppressive cytokines such as IL-10 and/or TGF-β, resulting in an anti-inflammatory environment. Even though this regulatory environment prevents the elimination of worms it also protects the host against excessive inflammation. In worm-infected mice, blocking the IL-10 receptor partly restores IFN-γ and IL-12 production in lamina propria mononuclear cells. Mice that cannot make IL-10 develop a chronic colitis driven by cytokines associated with Th1/Th17 responses (e.g., IFN-γ, IL-17, IL-12, IL-23), attesting to the importance of this cytokine for mucosal immune homeostasis. |
Helminth parasites stimulate a similar type of immune response to that induced by allergens (Th2 type response), but they also induce strong regulatory responses and in recent years there has been considerable interest in the potential role of helminth infections in modulating/regulating allergy risk in helminth-endemic areas. The underlying mechanisms are suggested to involve the regulatory presence of parasite-induced IL-10. |
Worm infection inhibits mucosal IL-23 and IL-17 secretion, suggesting that regulation of IL-17 is an important mechanism of colitis control. How helminths limit IL-17 (Th17) responses is not understood completely. However, blockade of IL-23 secretion and stimulation of IL-4 production at the mucosal surface plays a partial role. |
Gram-negative bacteria frequently express lipopolysaccharides (LPS). LPS interacts with receptors of the innate immune system (Toll-Like Receptor 4) on host cells, driving production of protective proinflammatory molecules. The normal intestinal mucosa usually is relatively unresponsive to LPS, since the normal intestinal flora produces large amounts of this molecule and uncontrolled responses to LPS would be dangerous for the mucosa. H. polygyrus infection induces display of TLR4 on a subset of mucosal T cells. Engagement of this receptor promotes production of regulatory (TGF-β, IL-10) rather than proinflammatory molecules. Thus, under the influence of helminths, damage to the mucosa allowing LPS penetration may induce activation of IL-10/TGF-β producing regulatory T cells, helping to quell excessive adaptive immunity. |
Trichuris suis is a helminth of the nematode family. When pigs, the preferred host, ingest embryonated eggs, larvae are released in the intestine and colonize the superficial portion of the cecal and colonic mucosa. No systemic invasion occurs, as the worms mature in the intestinal lumen. In the pig T. suis’ infection is mainly asymptomatic, except in piglets, in which it can cause diarrhea and prevent growth. |
Although human subjects are not the natural host for T. suis, it can survive for a few months in people without causing illness. |
Trichuris suis ova (TSO) were orally administered to patients with inflammatory bowel disease (Helminths and our immune system: friend or foe?, 2009). In all studies no adverse events were reported. |
Evidence of safety is also available from a study performed in patients with multiple sclerosis. One concern about the use of TSO as a therapy in humans is the possibility that egg preparations could contain other infectious agents often present in pigs, which are pathogenic in humans, such as hepatitis E virus. The TSO preparations used in all the recent clinical trials were systematically tested for multiple infectious agents according to procedures and processes approved by the FDA. This guarantees their microbiological safety. Another element contributing to the overall safety of using TSO as a therapy is the availability of anthelmintic drugs, such as albendazole or mebendazole, which are active against T. suis and are generally considered safe, including in children. These drugs could be used if a subject receiving TSO were to experience a TSO-related adverse event considered severe enough to require specific treatment.Overall, the evidence of safety of TSO is strong. The side effects have been absent o mild and spontaneously resolving. |
Because of the safety of T. Suis, Trichuris Suis Ova (TSO) were chosen as the therapeutic agent to start experimenting with. Pigs were infected with T. suis eggs, then adult worms were isolated from the infected animals and cultured in vitro. The worms survived long enough to produce eggs that could be harvested and cleaned for clinical use. |
Experiments in animals were eventually followed by pilot safety trials in humans in inflammatory bowel disease and allergic rhinitis. Subsequently, observational studies and exploratory clinical trials have been extended to multiple sclerosis. |
In murine models of autoimmune diseases, the presence of helminth infections has been shown to have a protective effect. In addition, helminths were found to be protective in several models of inflammatory bowel disease (IBD). |
Although the MRI results in this exploratory study are promising, particularly as they speak against an early, major anti-therapeutic effect of TSO in MS, they should be interpreted with caution, given the small number of subjects and the short period of observation. The favourable MRI results could be due to chance or regression to the mean; on the other hand, the “rebound” or return to the level of baseline activities after TSO administration was stopped suggests that a significant biological effect may be operative. |
To date, all phase 1 studies of helminth therapy in MS have shown excellent safety and some, but not all, have been encouraging with regard to effects on clinical outcomes, brain MRI measures and immune status. Nevertheless, it is essential to recall that the data from exploratory studies to date are very preliminary. |
It is not known how the helminths ingested may influence the central nervous system (CNS) in MS. An interesting observation was made by van der Valk and colleagues, who have provided compelling evidence that the first or earliest lesion of MS – before T cell invasion, breakdown of the blood-brain barrier and demyelination – is a small cluster of activated microglia, which they have called the pre-active lesion (PAL) of MS (van Noort et al., 2011 and Kipp et al., 2012). Furthermore, these investigators have shown that PAL are numerous and that their fate is variable; over a period of months some PAL will progress to classic plaques of inflammation and tissue damage, while others apparently will remain stable or even regress (van Horssen et al., 2012). These findings, if confirmed, would be of enormous importance, since they indicate that control of PAL fate may be the key to control of MS itself. Potentially, PAL are an attractive target for helminth immunomodulation mediated through the gut-systemic-CNS axis, e.g., by means of helminth-induced anti-inflammatory cytokines, other molecules, Tregs or additional cell types (Banks and Erickson, 2010) which may provide crucial modulating signals to microglial cells. Quite possibly, if immunomodulation by helminth or other agents favourably modifies CNS microglial PAL, MS itself will become quiescent. |
There is now little doubt that helminth infections really do have the ability to influence the development of immune responses. Both animal and human studies have demonstrated this repeatedly and convincingly. |
However, what remains to be established is if this ability is of any real public health significance. |
The stage of infection is likely to play a key role with respect to concurrent immune responses during a primary infection. Very little is known about the immune response during repeated helminth infections and even less of how such responses may affect concurrent immune responses. |
The wide, and sometimes contradictory, range of results reported from human as well as animal studies clearly suggest that the impact of helminth co-infections on the immune response is complicated and there is little knowledge regarding the interactions between these parasites and the immune system.The wide range of results reported from human co-infection studies probably depend on basic differences in study design, choice of statistics and differences in statistical power, the choice of drugs and intervention strategies as well as the type of assays and other immunological investigations. |
But it is also clear from animal studies that helminth species, timing and intensity of infections play major roles in the outcome of co-infections, and these factors have only recently begun to be considered in human studies. |