Introduction. Developed countries are experiencing an exponential increase in the incidence of

Transcription

1 HELMINTHES AND HUMANS 2 Introduction Developed countries are experiencing an exponential increase in the incidence of autoimmune and allergic diseases (McKay, 2009). This dramatic increase in autoimmune disorders such as type 1 diabetes, multiple sclerosis (MS), rheumatoid arthritis, and Crohn s disease may be explained by the Hygiene Hypothesis. The Hygiene Hypothesis implies that reduced exposure to microorganisms during childhood may contribute to abnormal immune regulation (Fleming et al., 2011). Humans and parasites have co-evolved over millions of years playing a significant role in shaping the human immune system (Zaccone, Fehervari, Phillips, Dunne, & Cooke, 2006). The Hygiene Hypothesis has led to examinations of how parasites manipulate their host s immune system and protect them from inflammatory and autoimmune diseases. Current research has studied various autoimmune disorders using diverse parasites. Studies have shown that helminthes inhibit T helper 1 (TH1) cell responses and initiate a nonautoimmune-disease promoting TH2-cell response (Dunne and Cooke, 2005). This proposes the possibility of using helminthes for the treatment and prevention of autoimmune diseases. The following five literature reviews demonstrate how the hypothesis is being investigated and how the results might be implemented. Review of Literature An article by Seppa (2011), explains that parasitic worms and humans share a coevolution over a millennia. The parasites that survived initial contact with humans (roundworms and flatworms) had to evolve to make the human host hospitable and thus developed mechanisms to suppress inflammation in response to their presence. The research presented in this article focuses on the correlation between helminth infection and diminished autoimmunity responses. Three case studies were presented; toddlers with asthma in Ethiopia, Argentinean

2 HELMINTHES AND HUMANS 3 multiple sclerosis (MS) patients, and schoolchildren in Gabon who were part of a dust mite allergy study. The toddler study observed that children living in relatively clean conditions were twice as likely to have asthma symptoms than toddlers in unsanitary conditions. Toddlers with roundworm infections also had fewer asthma symptoms than those without the infection. In Argentina, physicians Jorge Correale and Mauricio Farez performed a study of MS patients that were infected with helminthes against a similar group of MS patients without the infection. After four years of observation they discovered that the MRI scans of the infected MS patients showed 14 brain lesions, while those not infected had 164. The allergy study in Gabon, conducted by Maria Yazdanbakhsh, involved 317 schoolchildren infected with various intestinal worms, but with no dust mite allergies. Half were treated for the parasites while the others remained infected. Fourteen percent of the children treated for the helminth infection tested positive for the dust mite allergy as evidenced by a skin prick test as opposed to a less than 7% percent allergy rate for those not treated. In addition to case studies the article also presented the molecular mechanisms that parasitic worms use to attenuate autoimmune responses. In response to infection, interleukin-10, an immune messenger protein, is produced. Researchers believe that this protein is a corrective mechanism that slows down the immune system after the system has attempted to eradicate an antigen. Other anti-inflammatory agents garnering interest from researchers are regulatory T cells (T-regs), which are normal T cells that morph into T-regs when a parasitic infection activates the Foxp3 protein (Neppa 2011). To further explain the mechanism phenomenon, another article of interest to this study pursued research aimed to determine whether worm infection protects against type-1 diabetes in

3 HELMINTHES AND HUMANS 4 non-obese diabetic (NOB) mice (Hubner, Mitre, & Stocker, 2009). The results indicated that the mice infected with the L. Sigmodontis worms had pancreases with non-infiltrated islets and blood glucose averages of less than 230 mg/dl. The study concluded that helminth-mediated protection against autoimmunity is associated with increases in numbers of natural T-regulatory cells and that helminth infections can induce a Th2 shift in auto antigen-specific antibody production. This shift causes Th1 cells, which would otherwise destroy the beta cells in the pancreas, to morph into Th2 cells or regulatory cells. While the exact mechanism for this antibody production is elusive, the researchers hypothesize that the regulatory T cells interleukin-10, CD4+, CD25+, and Fox3P+ all play vital roles in the Th2 shift (Hubner, et al., 2009) Fleming et al. (2011) further examined the hygiene hypothesis through a safety and efficacy study of the effects of helminthes on relapsing and remitting MS patients. Twenty-five thousand T. suis (porcine whipworm) ova (TSO) were administered in a 15mL sterile phosphate buffered saline solution. Test subjects claimed that this solution was slightly salty and compared it to a sports drink. Even though, this was only the first phase of an investigational study the results were promising. There were no relapses or negative changes in MS related conditions and only a few complaints of mild gastrointestinal symptoms. MRI results showed the mean number of new lesions were 6.6 at baseline screening, 2.0 at three months of TSO treatment, and 5.8 at two months after treatment ceased. Interleukin-4 and interleukin-10 levels were elevated in most of the subjects. Contrary to the positive findings of the previous studies a population-based cohort study in Denmark conducted by Bager, Hansen, Wohlfahrt, & Melbye (2011) discovered that pinworm infection does not reduce autoimmune diseases such as asthma, type I diabetes, arthritis, or inflammatory bowel disease. The study followed 924,749 children born in Denmark between

4 HELMINTHES AND HUMANS and Of these children, 132,383 filled a prescription for Mebendazole to treat E. vermicularis while another 102,482 had a sibling who filled a prescription. The rest of the 689,884 children formed the reference group. 10,352 children in the reference group were identified as having an autoimmune disease. Using incidence rate ratios, it was determined that pinworm infection does not reduce autoimmune disease. Falcone and Pritchard (2005) summarized the potential risks and benefits associated with using parasitic worms as an autoimmune therapy. Since helminthes co-evolved with humans, it is believed that once the mechanism is established and testing begins in earnest there will be less attrition when tested for safety and side effects such as gastrointestinal distress. These potential benefits are shadowed by genuine health risks. The primary consideration is the selection of the right helminth. Worms that cannot establish themselves in the host is the safest option since the worms are readily cleared from the body. The problem with this is that frequent dosing would be required. Worms that can colonize and persist for long periods are favorable, but selection of known asymptomatic helminthes must persist over others. Furthermore, people who are immunocompromised should not be considered for helminth therapy due to possible helminth antigenic effects. Discussion The argument can be made that helminthes and humans were meant to live together in order to propagate each other's species. As seen in all but one study mentioned, subjects with parasitic worm infections fared better than their hygienic counterparts. The Denmark study which discredits the hygiene hypothesis claim was not a direct case study but a cohort study based on data gathered through observation. The challenges facing this theory moving forward are identifying the specific autoimmune attenuation mechanism that these worms exhibit and

5 HELMINTHES AND HUMANS 6 methods in which to administer the treatment. In the meantime, people diagnosed with autoimmune disorders have been testing the hygiene hypothesis on their own and unregulated. Great care must be taken when introducing a known antigenic substance into the body. As stated in literature, the right worm must be chosen, otherwise the potential for pathogenesis is wide open. Ingesting copious amounts of parasitic worms has become an unnatural process in the developed world. As such, the more accepted method of therapy might be in the form of inoculation with the worm's mechanism and not taking in the worms by mouth. Common Forms and Dosages A wide range of helminth pathogens can be immunoprotective thus forms and dosages vary in helminth studies and treatments. The helminthes used for treatment are those that naturally colonize in humans and animals, and protect humans from an increased Th1 response (Weinstock et al., 2010). The studies mentioned previously used T. suis ova, L. sigmodontis, and various roundworms. A. lumbricoides, T. trichiura, N. americanus, T. spiralis, T. solium, T. spiralis, and H. polygyrus are other examples of parasitic worms studied for autoimmune diseases. Specific helminthes tend to be used for specific disorders. For example, T. suis decreases symptoms for Crohn s disease, H. polygyrus prevents autoimmunity in inflammatory bowel disease, and S. mansoni eggs show autoimmunity protection in type 1 diabetes. (McKay, 2009). The parasite in the form of an egg, cercariae, or larvae may be given to patients orally or parenterally. The form of the infection depends upon the natural life cycle of the parasite selected. For example, Fleming et al. (2011) used oral solutions of 2,500 T. suis ova and 15 ml sterile phosphate buffered saline solution to create a helminth treatment for patients with MS

6 HELMINTHES AND HUMANS 7 In general, 50 to 50,000 parasites are administered to individuals with autoimmune diseases for treatment (Weinstock et al., 2010). The amount of eggs used are 500 to 5,000, extracts equal 100 micrograms to 10,000 micrograms, and larvae and cercaria dosages vary from 500 to 5,000. The amount of eggs in the stool after treatment help determine proper dosages by assessing the adequacy and intensity of the infection. Th1 and Th2 responses also reveal the efficacy of the parasite administration. For example, Mortimer (2006) conducted a study to determine the number of hookworm larvae necessary to achieve a load of 50 eggs/g in human stool for therapeutic trails of asthma. 10, 25, 50, or 100 N. americanus larvae were applied to a patch of skin on the arm. Dosages consisting of 10 N. americanus larvae resulted in at least 50 eggs/g in the stool and were well tolerated. Side Effects More research and studies need to be completed to determine all of the potential side effects of helminth treatments. Areas of concern are immune suppression by the parasites may increase the risk of infections or live helminthes may cause severe immune pathology such as vomiting and diarrhea. Choices of parasites are important in preventing side effects. S. mansoni may be harmful because of its long, survival rate in humans. T. suis may synergize with other pathogens for example, Campylobacter jejuni, and are also invasive and could migrate into vital organs. The potential risks must be compared to the serious adverse effects of current therapies for autoimmune diseases such as long-term steroid use and immunosuppressant. With continued research more information on potential side effects will be revealed. Conclusion The dramatic rise in autoimmune disorders of developed countries has led to the development of the Hygiene Hypothesis. This theory has been researched to develop alternative

7 HELMINTHES AND HUMANS 8 treatment therapies for those suffering from autoimmune diseases. The studies analyzed show promise for using helminthes as therapeutic agents. Precaution must be taken, though, when using pathogens to treat disease and more research should be completed to determine potential adverse effects.

8 HELMINTHES AND HUMANS 9 Works Cited Bager, P., Hansen, A.V., Melbye, M., & Wohlfahrt, J. (2011). Helminth infection does notreduce risk for chronic inflammatory disease in a population-based cohort study. Gastroenterology. Retrieved October 13, 2011, from Dunne, D.W. & Cooke, A. (2005). A worm s eye view of the immune system: consequences for evolution of human autoimmune disease. Nature Reviews Immunology. 5(5), Retreived from EBSCOhost. Falcone, F.H., Pritchard, D. (April 2005). Parasite role reversal: worms on trial. Trends in Parasitology, 21(4) Retrieved from EBSCOhost. Fleming et al. (2011). Probiotic helminth administration in relapsing remitting multiple sclerosis: a phase 1 study. Multiple Sclerosis ( ), 17(6), Retrieved from EBSCOhost. Hübner, M. P., Thomas Stocker, J. J., & Mitre, E. (2009). Inhibition of type 1 diabetes in filariainfected non-obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells. Immunology, 127(4), Retreived from EBSCOhost. McKay, D. (2009). The therapeutic helminth. Evolutionary Parasitology, 25(3), Mortimer, K. (2006). Dose-ranging study for trials of therapeutic infection with necator americanus in humans. The American journal of tropical medicine and hygiene, 75(5), 914. Retrieved from EBSCOhost. Seppa, N. (2011). Worming your way to better health. Science News, 179(3), Retrieved from EBSCOhost.

9 HELMINTHES AND HUMANS 10 Weinstock et al. (2010). Use of parasitic biological agents for prevention and control of autoimmune disease. United States Patent. Retrieved from &oi=fnd&dq=weinstock+use+of+parasitic+biological+agents+for+prevention+and+con trol+of+autoimmune+disease&printsec=abstract#v=onepage&q=weinstock%20use%20 %20parasitic%20biological%20agents%20for%20prevention%20and%20control%20of 20autoimmune%20disease&f=false.