New therapeutic target for the treatment of multiple sclerosis



    Researchers prove the role of certain leukocyte cell adhesion molecules
    in the pathogenesis of the disease

    MONTREAL, Jan. 22 /CNW Telbec/ - A study published in the February issue
of Nature Immunology provides answers about the role of novel adhesion
molecules in the pathogenesis of multiple sclerosis (MS) and suggests new
therapeutic targets for its treatment.
    The study, by the team of neurologist Dr. Alexandre Prat, neurologist,
researcher at the Centre hospitalier de l'Université de Montréal and professor
at the Faculty of Medicine of Université de Montréal, reveals that the
adhesion molecule, dubbed ALCAM (Activated Leukocyte Cell Adhesion Molecule),
or CD166, which is expressed by the endothelial cells of the brain, plays a
major role in the migration of certain types of leukocytes to the brain.
Researchers believe that the molecule constitutes a novel target to restrict
migration of immune cells to the brain, thus dampening neuroinflammation and
decreasing the lesions characteristic of MS. MS is a chronic autoimmune
disease of the nervous system that affects approximately 55,000 young adults
in Canada.
    Understanding the molecular mechanisms of brain inflammation is essential
in the development of new treatments for this degenerative disease. The study
was carried out also with researchers at McGill University (Dr. S. David),
Université de Montréal (Dr. N. Arbour), the National Research Council of
Canada (Dr. D. Stanimirovic) and University of Zurich (Dr. B. Becher).
    The results clearly demonstrate that CD166/ALCAM is involved in the
inflammatory process by priming the migration of leukocytes across the
blood-brain barrier (BBB). The research project combines results using 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(1), 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," states 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, thus
significantly decreasing 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
thus 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.

    Multiple Sclerosis

    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.

    About the Centre hospitalier de l'Université de Montréal (CHUM)

    www.chumontreal.qc.ca

    About Université de Montréal

    www.umontreal.ca

    --------------------------
    (1) Kebir H., Kreymborg K., Ifergan I., Dodelet-Devillers A., Cayrol R.,
    Bernard M., Giuliani F., Arbour N., Becher B., Prat A. Human TH17
    lymphocytes promote blood-brain barrier disruption and central nervous
    system inflammation (2007). Nat Med, 13(10), 1173-5.




For further information:

For further information: Nathalie Forgue, Communications Advisor, Centre
hospitalier de l'Université de Montréal (CHUM), (514) 890-8000, extension
14342; Sylvain-Jacques Desjardins, International press attaché, Université de
Montréal, (514) 343-7593, sylvain-jacques.desjardins@umontreal.ca; Sources:
Alexandre Prat, M.D., Centre hospitalier de l'Université de Montréal,
Université de Montréal; Nicole Beaulieu, M.A., APR, Director of
Communications, Centre hospitalier de l'Université de Montréal (CHUM)

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Centre hospitalier de l'Université de Montréal (CHUM)

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