Background:
In the 1980s Niel 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% Venezuelan Indians, living in the rainforest had worms but no allergies while the richest Venezuelans, living in the cities, 10% had light worm infections but 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 epidemiology was further elaborated by Joel Weinstock and his colleagues at the University of Iowa. This work attempted to explain how the process of urbanization, sanitation, advances in public health and medicine had resulted in a spike of diseases of immune dysfunction in the wealthy countries with particular emphasis on the eradication of intestinal worms. The wealth gradient was a complementary aspect to another theory called the hygiene hypothesis. The hygiene hypothesis arose from work in the late 1980s that attempted to explain a similar phenomenon of immune function with regard to family size.
These theories were elevated from theoretical framework to clinical importance when Joel Weinstock and his colleagues at the University of Iowa infected seven people with ulcerative colitis and Crohn's disease, who were non-responsive to traditional therapy, with Trichusus suis (pig whipworm). 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. One of the reasons that pig whipworm was selected for the original study was the belief that it could not colonized the human intestinal tract. Subsequently, case reports have emerged that contradict that belief.
Another significant aspect of the Weinstock study was that it hinted towards a refinement of the hygiene hypothesis called the "old friends" hypothesis. "Old friends" suggested that the human immune system had evolved with certain organisms for so long that they had become mutalistically symbiotic. In other words, we had evolved around the presence of certain parasites and their absence could result in "abnormal" conditions. The consequence of this theory is that the first cause of some diseases of immune dysfunction may be caused by a lack of worms that live in the human digestive tract.
Researchers at the University of Nottingham tested this by treating asthma patients with human hookworm. Again, the results were dramatic with nearly 70% of the patients demonstrating improvement. In the meantime, additional studies were being published suggesting that the therapeutic benefit of the intestinal helminths might be broader than originally thought. Researchers in Argentina, concluded a five year study on multiple sclerosis (MS) and naturally acquired worm burdens that matched exacerbations in worm infected and non-worm patients. Over the course of five years the worm infected patients had three while the non-worm infected had 56.
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. The case is far from closed but a gathering body of evidence is pointing towards the conclusion that some of the intestinal worms may be probiotic.
Meanwhile, a little know researcher to the west Dr. Kichiro Fujita, in Japan, 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. In animal models tapeworms utilize a molecule similar to Transforming Growth Factor Beta to recruit regulatory T cells. One interesting side effect reported by Dr. Fujita was weight loss. Since tapeworms are competitors for host calories the report of weight loss in an individual responsive to helminthic therapy makes sense. A system optimized immunologically for the presence of worms would necessarily be metabolically adapted. Hence, the potential scope of the probiotic effects of the intestinal worms expands to obesity.
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. 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 understanding 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 failure of Interleukin 10 when administered systemically is a problem any pharmaceutical intervention is going to have to overcome. 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.
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.