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

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

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 Canada USA Australia Western Europe China Japan Malaysia African 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 infection (70 cercariae/mouse) Immunization with myelin glycoprotein Medical score + incidence Kill + count

Experimental Autoimmune Encephalomyelitis (EAE) Infection with S. mansoni decreased CNS inflammation Schistosomiasis seems to modify onset of EAE. MC= Unifected, immunized SMC = 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-10 IL-2

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

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 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.

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

Patient condition MRI parameters

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

CD4+/CD25+ = Regulatory T cells Th cells

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

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?

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 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.