New therapeutic target for treatment of MS

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New therapeutic target for treatment of multiple sclerosis

Researchers prove the role of certain leukocyte cell adhesion

molecules in the pathogenesis of the disease

http://www.eurekalert.org/pub_releases/2008-01/uom-ntt012108.php

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. andre 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.

), 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.

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.

On the Web:

About the Centre hospitalier de l'Université de Montréal:

www.chumontreal.qc.ca.

Read a comprehensive article on the Dr. andre Prat's research in

Forum at http://nouvelles.umontreal.ca/content/view/842/221/.

Sources:

andre Prat, M.D.

Centre hospitalier de l'Université de Montréal

Université de Montréal

Beaulieu, M.A., APR

Director of Communications

Centre hospitalier de l'Université de Montréal (CHUM)

Sylvain-Jacques Desjardins

International press attaché

Université de Montréal

Tel.: 514-343-7593