Theory

Background:

Helminthic therapy has emerged from extensive research indicating a probable connection between a reduction in parasitic worms in industrialized societies to a significant and sustained increase in autoimmune diseases and allergies. Conversely, the instances of these same diseases are relatively low in lesser developed countries where parasitic worms have not been reduced or eradicated.

In the 1980s Neil Lynch and his colleagues at the University of Venezuela correlated the absence of worms with the emergence of asthma and allergy in Venezuelans of varying economic background. His results showed that 90% of Venezuelan Indians living in the rainforest had worms and no allergies. Of the more affluent Venezuelans living in the cities, only 10% had light worm infections and 43% had allergies.

This distribution of worms vs. wealth has become known as the Wealth Gradient and it correlates the rise of affluence with the emergence of certain diseases of autoimmunity, asthma and allergy. This is a complementary aspect to a later development called the Hygiene Hypothesis. This explains the observation that hay fever and eczema, both allergic diseases, were less common in children from larger families, which were presumably exposed to more infectious agents through their siblings, than in children from families with only one child. The Hygiene Hypothesis was further refined into the "Old Friends" hypothesis, which suggests that the human immune system had evolved with certain organisms for so long that they had become mutualistically symbiotic. In other words, we had evolved around the presence of certain parasites and that their absence could result in "abnormal" conditions.

Joel Weinstock and his colleagues at the University of Iowa are integral developers of this epidemiology. Their studies showed how increased urbanization, sanitation, and medical and public health advances may have been connected to the spike of diseases of immune dysfunction. More pointedly, the eradication of intestinal worms, with which humans coexisted throughout much of our evolutionary history, caused our immune systems to become irregular and unbalanced. These theories were elevated to clinical importance when Weinstock treated seven patients that had ulcerative colitis and Crohn's Disease. Non-responsive to traditional therapy, they were then infected with pig whipworm (Trichurus Suis). The results of these phase I trials were remarkable. More than 70% of initial patients reported improvement. These findings launched a new field of intervention of polarized Th1/Th2 diseases called the low tech biologics. The principle was the use of whole organisms to treat diseases of autoimmunity, allergy and asthma. This breakthrough was licensed to Ovamed and later Biomonde.

Researchers at the University of Nottingham have begun the work of establishing a safe dose in asthma patients with human hookworm, the results of which are pending publication. In the meantime, additional studies were being published suggesting that the therapeutic benefit of the intestinal helminths might be broader than originally thought.

In Argentina, scientists have published a study claiming that some symptoms of Multiple Sclerosis may be lessened in people whose immune system has been affected by a parasite. The scientists studied 24 people with MS for more than four years, half of whom became infected with parasites after they were diagnosed with MS. Among the patients with parasites, there were only three clinical relapses, compared with 56 in the non-infected group.

In Japan, Dr. Koichiro Fujita began publishing his experiences of self-inoculation using a species of tapeworm. His experiments were consistent with those of Nottingham. He experienced relief from allergies, and also suspected that the tapeworm helped keep him slim. Logical, since tapeworms compete for the calories that the host ingests. A system optimized immunologically for the presence of worms would necessarily be metabolically adapted. Thus, type 2 diabetes may also be included in the potential scope of the beneficial effects of the intestinal worms.

Since Crohn's and MS share a common mechanism of Th1 predominate autoimmunity, the theoretical reach of this treatment spread to psoriasis, Grave's disease, rheumatoid arthritis, lupus, scleroderma and type I diabetes. A gathering body of evidence is pointing towards the idea that some of the intestinal worms may be probiotic, meaning the parasite is beneficial to its host. Still, there is much experimentation and research to be completed before we can call the results conclusive.

Mechanism:

The best described mechanism is that found in the animal models of colitis. In the mouse model of colitis the introduction of certain helminths reversed the disease process through an Interleukin 10 dependent pathway. This pathway seems to be mediated by recruitment of regulatory T cells CD25+ Fox3p+. What is instructive is the experience in humans with a non human worm. While pig whipworms are among the most potent stimulators of mucosal Th2 response they are not directly activating regulatory T cells. Instead the polarization of the Th2 response has inhibitory effects on the Th1 response through a mechanism not completely known. This discussion has ignored the role of the mysterious regulatory B cell and all of its implications. A description of the whole mechanism eludes us as of now, but it will likely be interplay between these mediators and possibly some still unknown.

While a complete elucidation of the mechanism of helminth human immune modulation will certainly afford a bounty of opportunity for pharmaceutical interventions in autoimmunity and allergic conditions our present understand is best explained as a valley created between the Th1/Th2 responses by the worms to create a suitable environment for their sustained existence. Whether the worms are using a mechanism of Fox3p activation via transforming growth factor beta (TFG-B) in the ICOS- ICOS ligand pathway or modification of dendritic cells the overall effect is to dampen immune response to harmless or self- antigens.

One of the certain advantages of using intestinal worms is the delivery mechanism. By invading the intestinal mucosa the worms are able to micro-dose immune cells as they encounter them. The genetic modification of lacatobacillus lactis is an example of an ingenious way of replicating the worm's delivery mechanism. Additionally, many suffers of conditions treated by the monoclonal antibodies will be familiar with the disadvantages of systemic dosing; the skewing of cancer profile and opportunistic infection being among the most severe. In this regard, the worms have an advantage in dosing just enough to create a friendly host environment but not so much as to compromise host immune function.

Finally, one should not underestimate the importance of internal noisiness for optimizing signal-to-noise ratio (SNR) problems. A well studied phenomenon of enhancing SNR in biological sensing systems is the use of internal filtration. The presence of these relatively large and "noisy" organisms will undoubtedly be found to have important functions in the optimizing of overall or global immune function.

Papers:

We have compiled a list of paper that we feel are important to a broad understanding of these tharapies. This list is in no way comprehensive. It is a starting point and we encourage you to do additional research.

Falcone FH, Pritchard DI. Parasite Role Reversal: Worms on Trial. Trends in Parasitology 2005; 21(4):157-160.

Summers RW, Elliott DE, Urban JF, Jr., Thompson RA, Weinstock JV. Trichuris Suis Therapy for Active Ulcerative Colitis: A Randomized Controlled Trial. Gastroenterology 2005; 128(4):825-832.

Elliott DE, Summers RW, Weinstock JV. Helminths as Governors of Immune-Mediated Inflammation. International Journal for Parasitology 2007; 37(5):457-464.

Correale J, Farez M. Association between Parasite Infection and Immune Responses in Multiple Sclerosis. Annals of Neurology 2007; 61(2):97-108.

Lewis S, M. Antoniak, D. Pritchard and J. Britton. Mortimer, A. Brown, J. Feary, C. Jagger, S. Dose-ranging study for trials for therapeutic infection with Necator Americanus in humans. Am. J. Trop. Med. Hyg., 2006, 75(5), 914-20.

Reddy A, Fried B. The Use of Trichuris Suis and Other Helminth Therapies to Treat Crohn's Disease. Parasitology Research 2007; 100(5):921-927.

Van Riet E, Hartgers FC, Yazdanbakhsh M. Chronic Helminth Infections Induce Immunomodulation: Consequences and Mechanisms. Immunobiology 2007; 212(6):475-490.

Croese, J., J. O'Neil, J. Masson, S. Cooke, W. Melrose, D. Pritchard, R. Speare. 2006. A proof of concept study establishing Necator americanus in Crohn's patients and reservoir donors. Gut 55: 136-137.

Carvalho EM, Bastos LS, Araujo MI. Worms and Allergy. Parasite Immunology 2006; 28(10):525-534.

Kitagaki K, Businga TR, Racila D, Elliott DE, Weinstock JV, Kline JN. Intestinal Helminths Protect in a Murine Model of Asthma. J Immunol 2006; 177(3):1628-1635

Summers RW, Elliott DE, Weinstock JV. Therapeutic Colonization with Trichuris Suis. Archives of Pathology & Laboratory Medicine 2006; 130(12):1753; Author Reply 1753-1754.

Elliott DE, Summers RW, Weinstock JV. Helminths and the Modulation of Mucosal Inflammation. Current Opinion in Gastroenterology 2005; 21(1):51-58

Hunter MM, Wang A, Hirota CL, Mckay DM. Neutralizing Anti-IL-10 Antibody Blocks The Protective Effect of Tapeworm Infection in a Murine Model of Chemically Induced Colitis. J Immunol 2005; 174(11):7368-7375.

Ponsonby AL, Van Der Mei I, Dwyer T, Blizzard L, Taylor B, Kemp A, Simmons R, Kilpatrick T. Exposure To Infant Siblings During Early Life and Risk of Multiple Sclerosis. Jama 2005; 293(4):463-469.

Maizels RM, Balic A, Gomez-Escobar N, Nair M, Taylor MD, Allen JE. Helminth Parasites--Masters of Regulation. Immunological Reviews 2004; 201:89-116.

Mangan NE, Fallon RE, Smith P, Van Rooijen N, Mckenzie AN, Fallon PG. Helminth Infection Protects Mice from Anaphylaxis Via IL-10-Producing B Cells. J Immunol 2004; 173(10):6346-6356.

Summers R, Elliott D, Weinstock J. Trichuris Suis In The Therapy Of Inflammatory Bowel Disease: Summary of Two Clinical Studies Conducted in The Center for Digestive Diseases at the University of Iowa. University of Iowa Health Care 2004:1-6

Van Den Biggelaar AH, Rodrigues LC, Van Ree R, Van Der Zee JS, Hoeksma-Kruize YC, Souverijn JH, Missinou MA, Borrmann S, Kremsner PG, Yazdanbakhsh M. Long-Term Treatment of Intestinal Helminths Increases Mite Skin-Test Reactivity in Gabonese Schoolchildren. J Infect Dis 2004; 189(5):892-900.

Bashir ME, Andersen P, Fuss IJ, Shi HN, Nagler-Anderson C. An Enteric Helminth Infection Protects Against an Allergic Response to Dietary Antigen. J Immunol 2002; 169(6):3284-3292.

Elliott, D. E., J. J. Urban, C. K. Argo, J. V. Weinstock. 2000. Does the failure to acquire helminthic parasites predispose to Crohn's disease?. FASEB J. 14: 1848-1855.