1. Helminth Therapy Avity Norman ZOO-425

2. Overview  The Hygiene Hypothesis  Allergies and Autoimmune Diseases  Helminth Therapy: Worms as Medicine  Worm products  Live infection  Example: Multiple Sclerosis and Trichuris suis  The future of helminth therapy  References

3. The Hygiene Hypothesis  Incidence of immune disorders (allergies and autoimmune diseases) has dramatically increased in the developed world, correlating with increased sanitation and decreased incidence of microbial and parasitic diseases.  Strachan (1989) demonstrates that, within a household, children with more older siblings are less prone to allergies than children with fewer older siblings, and suggests that exposure to pathogens from older siblings is the cause.  Other studies have shown lower incidence of allergies and autoimmune disease among people who spent their childhoods on farms, in households with pets, or in developing countries (Jouvin & Kinet, 2012).

4. The Hygiene Hypothesis (Bach, 2002)

5. The Hygiene Hypothesis  Our immune genomes, or “immunomes,” have coevolved with pathogens and parasites (Khan & Fallon, 2013).  Normal immune system development allows the body to develop tolerance to harmless organisms, food, and other particles, as well as defense mechanisms against pathogens. In the absence of pathogens, the immune system is likely to develop abnormally (Jouvin & Kinet, 2012).

6. Helminth Therapy (Khan & Fallon, 2013)

7. Helminth Therapy : Worms as Medicine  Even after immune system has developed abnormally due to lack of early exposure, parasites can help it function more normally  Two ways used medically:  Controlled infection with live helminths  Helminth-derived products Image source: http://www.menshealth.com/health/immune-system- worms?fullpage=true#ixzz2FOMSZ7ul

8. Helminth Therapy: Worm Products  Give the body helminth antigens to effect the same immunomodulatory response without the presence of a live worm  Fasciola hepatica excretory and secretory products prevent Type 1 diabetes in mice, show promise for humans (Robinson et al., 2013)  Antigens from Ascaris and Schistosoma tested in mice (Bolstridge et al., 2011)  Proposed cancer treatment: inject tumors with worm products so that the immune system will attack them as it would a helminth (Frenoy, 2008)

9. Helminth Therapy: Worm Products  May be very specifically targeted, mechanisms studied in detail (Rzepecka et al., 2013)  Filarial cystatin suppresses grass pollen allergies in mice (Danilowicz- Luebert et al., 2013)  Glycoprotein ES-62 alleviates asthma in mice, shows promise for humans (Rzepecka et al., 2013)

10. Helminth Therapy: Live Infection  Usually nematodes  Trichuris suis (pig whipworm) and Necator americanus (New World hookworm) most commonly used  Cestodes and trematodes have also proven effective in animal trials  Schistosoma mansoni, Schistosoma japonicum, Fasciola hepatica, Hymenolepis diminutia, and Taenia crassiceps tested in mice; alleviated various murine immune disorders (Hernandez et al., 2013)

11. Helminth Therapy: Live Infection Image source: http://24.media.tumblr.com/0pr5GveTto1qxrzz1bi5hskFo1_400.jpg (Bolstridge et al., 2011)

12. Helminth Therapy: Live Infection  Necator americanus - New World hookworm  Administered to patients as filariform larvae  Clinical trial data show no significant effectiveness against allergic rhinitis (Croft et al., 2013)  Clinical trial data support effectiveness against Celiac disease (Croese et al., 2013) and inflammatory bowel disease (Weinstock, 2013) Image source:http://www.cdc.gov/parasites/hookworm/biology.html (top) http://www.studyblue.com/notes/note/n/intestinal-nematodes/deck/2040170 (bottom)

13. Helminth Therapy: Live Infection  Trichuris suis - pig whipworm  Administered to patients as eggs (TSO = Trichuris suis ova)  Human infection always asymptomatic (Jouvin & Kinet, 2012)  Clinical trial data show no significant effectiveness against allergic rhinitis (Croft et al., 2013)  Clinical trial data support effectiveness against inflammatory bowel disease (Weinstock, 2013) and multiple sclerosis (Fleming, 2013) Image source: http://www.the-scientist.com/?articles.view/articleNo/29485/title/Opening-a-Can-of-Worms/ (top) http://a57.foxnews.com/global.fncstatic.com/static/managed/img/Health/0/371/TSO.jpg (left)

14. Multiple Sclerosis and Trichuris suis  Dysregulated T cells attack myelin  Typically begins when the patient is in mid-20s  Lifespan shortened by 5-10 years, progressively worsening disability throughout life  No known cure, treatments often limited in effectiveness and poorly tolerated by patient  Multiple sclerosis (MS) is a debilitating autoimmune disease of the central nervous system (Fleming, 2013)

15. Multiple Sclerosis and Trichuris suis  Genetic and environmental factors both contribute to the risk of multiple sclerosis  Strong correlation between low incidence of helminth infection and high risk of MS (Fleming, 2013)

16. Multiple Sclerosis and Trichuris suis  12 MS patients with naturally-occurring, asymptomatic intestinal helminth infection (various nematodes and cestodes) and 12 MS patients without intestinal worms were monitored for 7 years  After 4.6 years, attacks and lesions increased by 95% in the uninfected group  Infected group suffered almost no attacks, new lesions, or increase of disability  After 5 years, four of the infected patients were treated with antihelminthic drugs  Parasites were eliminated, and MS progression returned  Observational study on the effect of helminth infection on MS (Fleming, 2013)

17. Multiple Sclerosis and Trichuris suis  Three studies completed, each with 4 to 10 patients given 2500 T. suis ova every two weeks for 3 to 6 months  Safety of TSO treatment confirmed  Patients seemed to have suspended progression of disease while infected with worms, and to return to normal disease progression when infection clears  Results of treatment appeared favorable, but inconclusive due to small sample size and short trial duration  Exploratory clinical trials on the effect of Trichuris suis infection on MS (Fleming, 2013)  Phase 1 and 2 clinical trials now in progress, with 15 to 50 patients over 10 to 12 months

18. The Future of Helminth Therapy  Helminth therapy shows great promise in treating a variety of immune disorders  Could potentially also be used as a preventative measure Image source: http://eol.org/data _objects/2253333 1 (right) http://carycitizen.c om/wp- content/uploads/2 013/10/medicine- drop.jpg (left)

19. The Future of Helminth Therapy  Commercialization  Helminth therapies will not become widely available until pharmaceutical companies decide to produce them  The squick factor - would YOU want worms in your gut?  Many obstacles still to overcome:  More science!  Animal testing, observational studies, clinical trials (Tilp et al., 2013)

20. textbos References  Bach, J.F. 2002. The effect of infections on susceptibility to autoimmune and allergic diseases [Electronic version]. New England Journal of Medicine, 347(12): 911-20.  Bolstridge, J., Fried, B., & Reddy, A. 2011. Helminth Therapy to Treat Crohn’s and Other Autoimmune Diseases. In: H. Mehlhorn (Ed.), Parasitology Research Monographs [Electronic version] (pp. 211-225). Düsseldorf: Springer.  Croese, J., Gaze, S., & Loukas, A. 2013. Changed gluten immunity in celiac disease by Necator americanus provides new insights into autoimmunity [Electronic version]. International Journal for Parasitology, 43(3-4): 275-282.  Croft, A.M., Bager, P., & Garg, S.K. 2013. Helminth therapy (worms) for allergic rhinitis (Review) [Electronic version]. The Cochrane Collaboration, 6: 1-46.  Danilowicz-Luebert, E., Steinfelder, S., Kühl, A., Drozdenko, G., Lucius, R., Worm, M., Hamelmann, & E., Hartman, S. 2013. A nematode immunomodulator suppresses grass pollen-specific allergic responses by controlling excessive Th2 inflammation [Electronic version]. International Journal for Parasitology, 43(3-4): 201-210.  Fleming, J.O. 2013. Helminth therapy and multiple sclerosis [Electronic version]. International Journal for Parasitology, 43(3-4): 259-274.  Frenoy, G. (2008). U.S. Patent No. 7,33,354 [Electronic version]. Washington, DC: U.S. Patent and Trademark Office.  Hernandez, J.-L., Leung, G., & McKay, D. 2013. Cestode regulation of inflammation and inflammatory diseases [Electronic version]. International Journal for Parasitology, 43(3-4): 233-243.  Jouvin, M.-H. & Kinet, J.-P. 2012. Trichuris suis ova: Testing a helminth-based therapy as an extension of the hygiene hypothesis [Electronic version]. Journal of Allergy and Clinical Immunology, 130(1): 3-10.  Khan, A. & Fallon, P. 2013. Helminth therapies: translating the unknown unknowns to known knowns [Electronic version]. International Journal of Parasitology, 43(3-4): 293-299.  Robinson, M., Dalton, J., O’Brien, B., & Donnelly, S. 2013. Fasciola hepatica: The therapeutic potential of a worm secretome [Electronic version]. International Journal for Parasitology, 43(3-4): 283-291.  Strachan, D. P. 1989. Hay fever, hygiene, and household size. British Medical Journal, 299: 1259-1260.  Tilp, C., Kapur, V., Loging, W., & Erb, K. 2013. Prerequisites for the pharmaceutical industry to develop and commercialise helminths and helminth-derived product therapy [Electronic version]. International Journal for Parasitology, 43(3-4): 319-325.  Weinstock, J. 2013. Translatability of helminth therapy in inflammatory bowel diseases [Electronic version]. International Journal of Parasitology, 43(3-4): 245-251.  Rzepecka, J., Seibeke, I., Coltherd, J., Kean, D., Steiger, C., Al-Riyami, L., McSharry, C., Harnett, M., & Harnett, W. 2013. The helminth product, ES-62, protects against airway inflammation by resetting the Th cell phenotype [Electronic version]. International Journal of Parasitology, 43(3-4): 211-223.