WORM THERAPY: MULTIPLE SCLEROSIS

Rodrigo Ortega

Outline Introduction Multiple sclerosis: epidemiology and

mechanisms The hygiene hypothesis Experiments with animal models Results from a clinical study Conclusion and future challenges

IntroductionWorm therapy will be reviewed as a model of:

Immunopathology of parasitic infectionThe link between autoimmune diseases (e.g. MS) and mechanisms of parasitic infectionContext dependent outcome

Multiple Sclerosis (MS)

Progressive autoimmune disease

Development of many areas of hard scar tissue and inflammation

Symptoms: blurry vision*, muscular weakness, numbness, tremor, ataxia.

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?

Trichuris trichiura and the hygiene hypothesis

Each point represents a country

CanadaUSAAustraliaWestern Europe

ChinaJapanMalaysiaAfrican countries

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.

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?

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.

Experimental Autoimmune Encephalomyelitis (EAE)

Experimental Autoimmune Encephalomyelitis (EAE) Infection with S. mansoni decreased CNS

inflammation Schistosomiasis seems to modify onset

of EAE.MC= Unifected, immunizedSMC = Infected, immunized

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-10IL-2

Th1 vs. Th2

Th1-mediatedActivates macrophages against myelin basic protein

Strong Th2 response

Stimulates the production of antibodies and anti-parasitic WBCs

Autoimmunity (MS) Parasitic infection

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?

Clinical study

Argentine study (Correale and Farez, 2007)

Design

12 Healthy

(No MS or infection)

High WBC count

Methods ~ 5 years

MRI parameters

Patient condition

IL-10

IL-2

p <0.0001 p <0.0001

p=0.0001. p =0.0001

CD4+/CD25+ = Regulatory T cells

CD4+/CD25- = Th cells

In a nutshell…

Patient condition improved

MRI parameters look better

More regulatory T-cells

Th2 response anti-inflammation

Correale and Farez, 2007

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?

STRENGTHS WEAKNESSES

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?

Future challenges

Do you want fries with this?wormtherapy.com

Avoidance of tissue invasion, effects of co-infections,effects specific to different life stages of the agent, unforeseen consequences of xenoinfection

References

Correale, J., Farez, M. 2007. Association between parasite infection and immune responses in Multiple Sclerosis. Ann. Neurol. 61: 97-108.

Fleming, JO, Cook TD. 2006. Multiple sclerosis and the hygiene hypothesis. Neurology. 67:2085-2086.

Fleming JO, Fabry Z. 2007. The hygiene hypothesis and multiple sclerosis. Ann Neurol. :85-89.

References

La Flamme AC, Ruddenklau K, Bäckström BT. 2003. Schistosomiasis decreases central nervous system inflammation and alters the progression of experimental autoimmune encephalomyelitis. Infect. Immun. 71:4996-5004.

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. 2005. J Exp Med. 202:1319-25.