Cleanliness is overrated
In 1989, British epidemiologist David P. Strachan reported a relationship between decreasing family size and increasing incidence of allergies in industrialized countries, suggesting that early exposure to germs spurs the development of a strong immune system. This framed the basis for the “hygiene hypothesis”, which in recent years has been expanded to include the “old friends” hypothesis. The “hygiene hypothesis” indicates that a shift towards living in a more sanitary environment has resulted in fewer early-life infections with organisms that play a crucial role in the development of our immunoregulatory pathways. The “old friends” theory further suggests that the specific absence of organisms with which we co-evolved has resulted in a failure to regulate inappropriate immune responses, leading to the development of allergies or autoimmune diseases. Could we therefore decrease the incidence or severity of autoimmune disease by introducing these organisms into humans later in life?

The early host catches the worm
Studies have shown that infection with helminths can protect against the inflammation associated with allergy and autoimmunity. In areas of the world where helminth infections are still common, a lower incidence of allergies and autoimmune conditions has been observed. Helminths include many types of multicellular parasitic worms that mainly reside in actively infected tissues. Unlike other pathogens, helminths do not proliferate within their hosts, but instead develop slowly while maintaining chronic infections. Thus, helminths have a long history of co-evolution with humans; they are usually well tolerated while modulating the host’s immune system to ensure their own survival and continued transmission. In contrast to traditional microbial pathogens, helminths typically induce a Type 2 (or Th2) immune response, which involves the production of cytokines including interleukin-4 (IL-4), IL-5, and IL-13. These Th2 cytokines mediate classical allergic-like inflammation, where IL-5 results in the recruitment of eosinophils and IL-4 activates B cell Ig class-switching for IgE production and basophil activation. Together, IL-4 and IL-13 can also polarize macrophages towards an alternatively activated, anti-inflammatory state. In clinically asymptomatic infected individuals, Th2 responses are observed alongside high levels of immunosuppressive cytokines such as interleukin-10 (IL-10). These cytokines are thought to be produced by expanded populations of regulatory cells including regulatory T cells (Tregs), regulatory B cells and alternatively activated macrophages.

Image Credit: Kieran Manion
Image Credit: Kieran Manion

A potential therapy
Given the ability of helminths to modulate the immune system, scientists are interested in the potential benefits that humans may obtain from hosting these parasites. Overwhelming evidence from animal models of multiple sclerosis (MS), ulcerative colitis, and Crohn’s disease has indicated that helminth infections can protect against these autoimmune diseases and reduce the associated inflammation and disease severity. Current investigations of helminth therapy have been conducted using two helminths with low pathogenicity in humans: Trichuris suis (pig whipworm) and Necator americanus (human hookworm). These worms can temporarily colonize human intestinal mucosa without causing major illness when multiple doses of helminth larvae are taken orally over a period of time. In particular, the helminth-induced immunomodulation therapy (HINT) clinical trials on newly-diagnosed MS patients, led by Dr. John Fleming, have garnered much interest. In MS, the overactive immune system attacks the nerves and causes inflammation of the brain and spinal cord. Preliminary data from phase 2 of the HINT trial has demonstrated that helminth therapy can be safe and is well tolerated in patients. Furthermore, the data suggest that helminth therapy is anti-inflammatory, inducing the expansion of Tregs and increased serum levels of IL-4 and IL-10. Thus, the HINT trial supports the idea that helminth therapy may be a safe and effective way of achieving clinical improvement and remission for specific autoimmune diseases.

Infection vs. cure
While the preliminary results for helminth therapy look promising, there are many limitations associated with the current clinical trials including small patient numbers and the choice of helminths used. As the helminth eggs used in current trials are manufactured in sterile environments, it is possible that the process of manufacturing may alter helminth vitality and the effects they have when in human hosts. As well, since patients would be dependent on treatment with live helminths, there is concern around co-infections with other pathogens that could result in serious illness, especially in immunocompromised individuals. Although helminth infections are associated with beneficial immunoregulatory effects, helminth infections are still a major healthcare concern, with more than two billion people currently infected worldwide. They can contribute to morbidity in adults, impair physical and cognitive development in children, and even result in death.

The main goal of current research in helminth therapy is to determine the mechanisms used by helminths to modulate the host immune system. Understanding these mechanisms will aid in the search for the key molecules derived from helminths that are responsible for their therapeutic effects. In animal models, secreted molecular products derived from helminths, including glycoproteins and lipoproteins, have been shown to have immunomodulatory properties. The identification and production of recombinant or synthetic versions of these helminth-derived products may overcome the problems associated with live helminth therapy. As helminth therapy can be used as an alternative to conventional immunosuppressants, the concept of harnessing helminths to treat autoimmune diseases is extremely alluring.


 

References

1. Fleming, J.O. (2013). Helminth therapy and multiple sclerosis. International Journal for Parasitology. 43: 259-274.

2. Fleming, J.O., Weinstock, J.V. (2015). Clinical trials of helminth therapy in autoimmune diseases: rationale and findings. Parasite Immunology. 37: 277-292.

3. La Flamme, A.C. (2015). The platinum age of parasitology harnessing the power of the parasite. Parasite Immunology. 37: 275-276.

4. Nutman, T.B. (2015). Looking beyond the induction of Th2 responses to explain immunomodulation by helminths. Parasite Immunology. 37: 304-313.

5. Shepherd, C., Navarro, S., Wangchuk, P., Wilson, D., Daly, N.L., Loukas, A. (2015). Identifying the immunomodulatory components of helminths. Parasite Immunology. 37: 293-303.

 

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Lindsay Cho

Lindsay Cho is a MSc student in the Department of Immunology studying the role of endogenous danger signals in the pathogenesis of autoimmune diseases. Outside of grad school, she enjoys playing the violin and watching movies.

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