1. Worm therapy: Multiple Sclerosis
Rodrigo Ortega

2. Outline Introduction Multiple sclerosis: epidemiology and mechanisms
The hygiene hypothesis
Experiments with animal models
Results from a clinical study
Conclusion and future challenges

3. Introduction Worm therapy will be reviewed as a model of:
Immunopathology of parasitic infection
The link between autoimmune diseases (e.g. MS) and mechanisms of parasitic infection
Context dependent outcome

4. Multiple Sclerosis (MS)
Progressive autoimmune disease
Development of many areas of hard scar tissue and inflammation
Symptoms: blurry vision*, muscular weakness, numbness, tremor, ataxia.

5. Epidemiology of MS More common in Caucasians (2X as likely)
Rare among certain groups (Africans, Asians)
More common in Northern latitudes with temperate climates (5X more prevalent)
The 2004 Alberta MS prevalence : 357.6/100,00
Rare in tropical and subtropical climates
How about the interactions with the environment?

6. Trichuris trichiura and the hygiene hypothesis
Each point represents a country
Canada
USA
Australia
Western Europe
China
Japan
Malaysia
African countries

7. Hygiene Hypothesis
Living in a highly sanitized environment during childhood is associated with a high prevalence of autoimmune diseases later in life.
The decline in infectious diseases could be associated with the increasing incidence of autoimmune diseases.

8. Mechanisms of autoimmunity
Deficiency of T-regulatory cell activity is a hallmark of autoimmunity.
T-regulatory cells supress the activity of the adaptive immune system.
What factors result in the lack of these cells?
How does parasitic infection alter these factors?

9. Model organisms #1
Schistosoma mansoni egg secretes a cytokine-binding protein with anti-inflammatory activity
Inhibits the binding of cytokines to receptors ultimately inhibiting cytokine biological activity.
Restitutes T-regulatory cell activity.

10. Experimental Autoimmune Encephalomyelitis (EAE)
Experimental infection
(70 cercariae/mouse)
Immunization with myelin glycoprotein
Medical score + incidence
Kill + count

11. Experimental Autoimmune Encephalomyelitis (EAE)
Infection with S. mansoni decreased CNS inflammation
Schistosomiasis seems to modify onset of EAE.
MC= Unifected, immunized
SMC = Infected, immunized

12. T helper cells (Th)
Known to express CD4 glycoprotein in their surface.
Th cells secrete cytokines that attract fresh macrophages, lymphocytes and other cytokines
Most important: Th1 and Th2
IL-10
IL-2

13. Th1-mediated Activates macrophages against myelin basic protein
Th1 vs. Th2
Autoimmunity (MS)
Parasitic infection
Th1-mediated Activates macrophages against myelin basic protein
Strong Th2 response Stimulates the production of antibodies and anti- parasitic WBCs

14. Could the regulatory T-cells induced during parasite infections alter the course of MS?
How are Th1 and Th2 altered in parasite- infected MS patients?

15. Clinical study
Argentine study
(Correale and Farez, 2007)

16. Design 432 patients Hymenolepis nana (3) Trichuris trichiura (3)12
MS no infection
MS + infection
Hymenolepis nana (3)
Trichuris trichiura (3)
Ascaris lumbricoides (3)
Strongyloides (2)
Enterobius (1)
High WBC count 12
Healthy
(No MS or infection)
Three patients were infected
with Hymenolepis nana, 3 with Trichuris trichiura,
3 with Ascaris lumbricoides, 2 with Strongyloides
stercolaris, and 1 with Enterobius vermicularis.

17. Methods ~ 5 years T-cell clone count Progress WBC count
Selection of patients
Stool analysis and egg count
Progress
Disability Score
MRI
Cytokine secreting cell count
T-cell clone count

18. Patient condition
MRI parameters

19. IL-10
p <0.0001
p <0.0001
IL-2 p=
p =0.0001

20. CD4+/CD25+ = Regulatory T cells
Th cells

21. In a nutshell… Patient condition improved MRI parameters look better
More regulatory T-cells
Th2 response  anti-inflammation

22. Correale and Farez, 2007 STRENGTHS WEAKNESSES
Interesting epidemiology -High parasite prevalence -Demographic composition Clinical study -MS symptoms assessed by physicians -Long term
Too few subjects?? What if the effect is more individual?

23. Conclusion
Potential therapy applications of anti-inflammatory side effects of parasitic infections to alleviate MS symptoms (evidence from mice and clinical studies)
Prevalence (and exposure) of parasites in highly- sanitized countries might indeed explain low prevalence of MS
Links between some steps of the immune mechanisms
Role of genetics? Diet?

24. Future challenges wormtherapy.com Do you want fries with this?
Avoidance of tissue invasion, effects of co-infections,
effects specific to different life stages of the agent, unforeseen consequences of xenoinfection

25. References
Correale, J., Farez, M Association between parasite infection and immune responses in Multiple Sclerosis. Ann. Neurol. 61: Fleming, JO, Cook TD Multiple sclerosis and the hygiene hypothesis. Neurology. 67: Fleming JO, Fabry Z The hygiene hypothesis and multiple sclerosis. Ann Neurol. :85-89.

26. References
La Flamme AC, Ruddenklau K, Bäckström BT Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect. Immun. 71:
Smith P, Fallon RE, Mangan NE, Walsh CM, Saraiva M, Sayers JR, McKenzie AN, Alcami A, Fallon PG. Schistosoma mansoni secretes a chemokine binding protein with antiinflammatory activity J Exp Med. 202: