Download Worm therapy: Multiple Sclerosis

WORM THERAPY:
MULTIPLE SCLEROSIS
Rodrigo Ortega
Outline
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Introduction
Multiple sclerosis: epidemiology and mechanisms
The hygiene hypothesis
Experiments with animal models
Results from a clinical study
Conclusion and future challenges
Introduction
Worm therapy will be reviewed as a model of:
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Immunopathology of parasitic infection
The link between autoimmune diseases (e.g. MS)
and mechanisms of parasitic infection
Context dependent outcome
Multiple Sclerosis (MS)
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Progressive autoimmune
disease
Development of many
areas of hard scar tissue
and inflammation
Symptoms: blurry vision*,
muscular weakness,
numbness, tremor, ataxia.
Epidemiology of MS
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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
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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
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Canada
USA
Australia
Western Europe
Each point represents a
country
China
Japan
Malaysia
African countries
Hygiene Hypothesis
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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
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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
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Schistosoma mansoni egg secretes a cytokine-binding
protein with anti-inflammatory activity
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Inhibits the binding of cytokines to receptors ultimately
inhibiting cytokine biological activity.
Restitutes T-regulatory cell activity.
Experimental Autoimmune
Encephalomyelitis (EAE)
Experimental
infection
(70 cercariae/mouse)
Kill +
count
Immunization
with myelin
glycoprotein
Medical score
+ incidence
Experimental Autoimmune
Encephalomyelitis (EAE)
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Infection with S. mansoni decreased CNS
inflammation
Schistosomiasis seems to modify onset of EAE.
MC= Unifected, immunized
SMC = Infected, immunized
T helper cells (Th)
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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-2
IL-10
Th1 vs. Th2
Autoimmunity (MS)
Th1-mediated
Activates macrophages
against myelin basic
protein
Parasitic infection
Strong Th2 response
Stimulates the production
of antibodies and antiparasitic WBCs
Could the regulatory T-cells induced
during parasite infections alter the course
of MS?
 How are Th1 and Th2 altered in parasiteinfected MS patients?
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Clinical study
Argentine study
(Correale and Farez, 2007)
Design
432 patients
High WBC count
12
MS no infection
12
Healthy
(No MS or infection)
12
MS + infection
Hymenolepis nana (3)
Trichuris trichiura (3)
Ascaris lumbricoides (3)
Strongyloides (2)
Enterobius (1)
Methods
WBC count
Selection of
patients
~ 5 years
Stool analysis
and egg count
Progress
Disability Score
MRI
T-cell clone
count
Cytokine
secreting cell
count
Patient condition
MRI parameters
p <0.0001
p <0.0001
IL10
p=0.0001.
p =0.0001
IL-2
CD4+/CD25+ =
Regulatory T cells
CD4+/CD25- =
Th cells
In a nutshell…
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Patient condition improved
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MRI parameters look better
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More regulatory T-cells
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Th2 response  anti-inflammation
Correale and Farez, 2007
STRENGTHS
WEAKNESSES
Interesting epidemiology
-High parasite prevalence
-Demographic composition
Too few subjects??
Clinical study
-MS symptoms assessed by
physicians
-Long term
What if the effect is
more individual?
Conclusion
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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 highlysanitized countries might indeed explain low
prevalence of MS
Links between some steps of the immune mechanisms
Role of genetics? Diet?
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
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.