Immunoregulation by Controlled Parasite Exposure in Multiple Sclerosis. (WIRMS-1)
The aim of the study is to determine whether controlled infection with a clinically safe number of larvae of hookworm results in an immune response that is protective in relapsing MS.
Biological: Live Hookworm Larvae
|Study Design:||Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Official Title:||Immunoregulation by Controlled Parasite Exposure in Multiple Sclerosis.|
- Primary outcome measure is an increase in the percentage from total CD4+ T cells of CD4+CD25+foxp3+ cells. [ Time Frame: End of study ] [ Designated as safety issue: No ]
- The expression of foxp3 mRNA from peripheral blood mononuclear cells (PBMC). [ Time Frame: End of study ] [ Designated as safety issue: No ]
- The percentage from total PBMC of NK and NKT cells (CD3-CD56+ and CD3+CD56+ respectively). [ Time Frame: End of study ] [ Designated as safety issue: No ]
- The percentage from total CD3+ T cells of Tr1 cells (CD3+IL10+ T cells). [ Time Frame: End of study ] [ Designated as safety issue: No ]
- The percentage from total PBMC of B regulatory cells (CD20+IL-10+). [ Time Frame: End of study ] [ Designated as safety issue: No ]
|Study Start Date:||February 2008|
|Study Completion Date:||May 2008|
|Primary Completion Date:||May 2008 (Final data collection date for primary outcome measure)|
Patients will receive 25 live hookworm larvae.
Biological: Live Hookworm Larvae
25 live hookworm will be applied to the arm and will infect transdermally. They will be eradicated after 48 weeks.
Placebo Comparator: 2
Patients will receive 0.01 % histamine solution.
0.01% histamine solution is pipetted onto a plaster dressing.
Studies have shown that there may be an inverse relationship between infections with worms including hookworms and inflammatory diseases including multiple sclerosis (MS). This has been explained by a protective immune reaction that is triggered by the hookworm in the body that dampens inflammation. In mice with MS, infections with some mouse worms reduced the inflammation and damage to their brain. The primary purpose of this study is to determine whether people with MS who are exposed to a small number of hookworms will develop this protective immune reaction that may reduce MS disease activity. We also plan to determine the effect of the hookworms on relapses during 1 year study.
A study of people with MS naturally infected with intestinal parasites did show significant protection over 5 years, and the levels of biological markers of the infection and some immune substances triggered by it were similar to the ones we obtained with controlled infection in normal volunteers, allergic and asthmatic peoples. We think the study has a genuine potential to benefit people with MS, and there is known interest in the MS patient community. At the therapeutic doses proposed here, this is an innocuous infection. Natural hookworm infection affects 1 billion people worldwide, often without symptoms unless the parasite load is very high. Our controlled exposure studies have shown good tolerability and safety; the risk of infecting others and auto-infection virtually is nil in Western standard hygiene conditions. Many people with MS when asked stated they would prefer an innocuous infection with microscopic larvae to a man-made product that may have more side effects. If the protective mechanisms are determined these studies may also lead to new ways of treating MS, possibly by selecting only the specific chemical components of the worms and the immune response to them that confer protection.
The increase in MS in the Western world, along with other autoimmune inflammatory diseases and asthma may be attributed to decreased exposure to infections such as gut parasites due to improved hygiene ('the hygiene hypothesis'). In animal models, controlled parasite infections including hookworms and related worms protect against MS-like disease. Parasites have evolved host-specific molecular mechanisms to dampen or condition the excessive immune responses against them and thus survive. These parasites induce regulatory mechanisms including Treg and a novel class of B cells that also dampen immune responses called Breg and were recently shown to improve MS in natural infection. They may suppress a class of lymphocytes that cause most damage in MS, Th17 cells. We will produce, with controlled exposure, a similar response to those associated with protective natural exposure in MS. We have the unique combination of expertise in hookworm biology, controlled parasite exposure and immunology of MS and MS trials and our data from our other human studies indicate this is a safe and tolerable intervention of significant potential.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00630383
|Nottingham University Hospital NHS Trust|
|Nottingham, Nottinghamshire, United Kingdom, NG7 2UH|
|Principal Investigator:||Cris Constantinescu, MD PhD||University of Nottingham|