Jan. 24, 2008 An international research team, led by a scientist from the Centre hospitalier de l'Université de Montréal (CHUM), has identified new therapeutic targets for the treatment of multiple sclerosis (MS). In the February issue of Nature Immunology, the team provides fresh answers concerning the role of novel adhesion molecules in the pathogenesis of MS, a chronic autoimmune disease of the nervous system that affects approximately 55,000 young adults in Canada.
Conducted by Dr. Alexandre Prat, a CHUM neurologist and researcher and a professor at the Université de Montréal's Faculty of Medicine, the study included collaborators from McGill University (Dr. S. David), the Université de Montréal (Dr. N. Arbour), the National Research Council of Canada (Dr. D. Stanimirovic) and University of Zürich (Dr. B. Becher). The team found that the adhesion molecule dubbed ALCAM (Activated Leukocyte Cell Adhesion Molecule), or CD166, plays a major role in the migration of certain types of leukocytes to the brain.
The researchers believe that the molecule, which is expressed by the endothelial cells of the brain, constitutes a novel target to restrict migration of immune cells to the brain, thereby dampening neuroinflammation and decreasing the lesions characteristic of MS. Understanding the molecular mechanisms of brain inflammation is essential in the development of new treatments for MS.
Dr. Prat and his team clearly demonstrate that CD166/ALCAM is involved in the inflammatory process by priming the migration of leukocytes across the blood-brain barrier (BBB). The investigation combined the results of an in vitro human BBB model and an in vivo experimental autoimmune encephalomyelitis mouse model. Normally, a limited number of immune cells are able to cross the BBB and penetrate the central nervous system.
In MS and other neuroinflammatory diseases, the increased permeability of the BBB is associated with an increase in the transmigration of some of these immune cells, which penetrate the central nervous system and cause the demyelinating lesions of MS. A previous study by Dr. Prat's team published in October in Nature Medicine, proved that a certain type of leukocyte, the TH17 lymphocyte, produces two critical products, interleukins 17 and 22 (IL-17 and IL-22), which contribute to infiltrating the blood-brain barrier and causing inflammation of the central nervous system.
"Blocking the migration of immune cells across the BBB has long been considered a promising therapeutic approach to autoimmune diseases of the central nervous system," said Dr. Prat. "This study has given us new insight into the factors involved in the pathogenesis of immune reactions affecting the central nervous system and allowed us to identify potential targets to suppress neuroinflammatory processes."
An attractive therapeutic target
Pharmacological agents exist that reduce the transmigration of immune cells by specifically blocking leukocyte adhesion molecules, which significantly decrease the extent of CNS inflammation. However, they also impede the immune system's ability to provide protection against chronic viral infections of the central nervous system, such as progressive multifocal leukoencephalopathy, a demyelinating disease of the central nervous system caused by the JC virus. Since ALCAM/CD166 blockade does not affect CD8+ T cell migration, whose main function is to destroy cells infected by viruses and neoplastic cells, the study results suggest that CNS immune protection against viruses would not be compromised by ALCAM blockade in vivo. ALCAM/CD166 could be considered as an attractive therapeutic target for multiple sclerosis.
This study was funded by the Multiple Sclerosis Society of Canada and by the Canadian Institutes of Health Research (CIHR).
The blood-brain barrier (BBB)
The BBB is a membranic structure that controls and limits exchanges between the blood and the brain. Composed of endothelial cells packed tightly within brain capillaries, it maintains the composition of the brain's interstitial spaces by its selective and restrictive permeability. It is almost completely impermeable to various molecules, immune cells and substances circulating in the blood. The BBB thus isolates and protects the brain from the rest of the organism.
In MS, immune cells penetrate the BBB and attack the myelin, a protective sheath that covers the nerve fibres of the central nervous system. The destruction of myelin causes loss of sensation, paralysis and handicaps. It is believed that genetic, infectious and environmental factors trigger MS, but the exact cause of the disease is still unknown. It affects twice as many women as men.
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