helminth therapy avity norman zoo-425. overview the hygiene hypothesis allergies and autoimmune...

Helminth Therapy

Avity Norman

ZOO-425

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

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).


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(Bach, 2002)


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).

Helminth Therapy



(Khan & Fallon, 2013)

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

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Image source: http://www.menshealth.com/health/immune-system-worms?fullpage=true#ixzz2FOMSZ7ul

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)

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)

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)




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


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)






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)

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)


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)


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)


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

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.com/wp-content/uploads/2013/10/me

dicine-drop.jpg (left)

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)

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.

helminth therapy avity norman zoo-425. overview the hygiene hypothesis allergies and autoimmune...

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