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Has anyone heard about the theory that the melanoma cell adhesion model (Mcam) is used by lymphocytes to access the CNS and that trials are planned for Prothena's antibody, PRX003, which is designed, to inhibit MCAM function and is hoped it will help sufferers of progressive ms? Is this a unique hypothesis? Is this a promising lead? Are trials for treatment of MS far off ?
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I found this... Thanks for the information
A molecule called melanoma cell adhesion molecule (MCAM) has been identified as a biomarker of disease activity in multiple sclerosis (MS) and a potential therapeutic target for MS and other neuroinflammatory conditions. In a new study in the journal Annals of Neurology, MCAM is shown to be important for allowing pathogenic CD8+ T lymphocytes to cross the blood brain barrier and access the central nervous system (CNS). Blocking MCAM reduced neurological deficits in a mouse model of MS, as well as restricting pathogenic CD8+ T lymphocyte migration across the blood brain barrier in an in vitro cell line model. The study was carried out by a research team led by senior author Dr. Alexandre Prat, of Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM) and professor in the Department of Neurosciences at the University of Montreal.
MS is a devastating neurological disease characterized by paralysis, numbness, vision loss and deficits in gait and balance. Typically, it develops in two phases. The first phase features outbreaks of symptoms with intervening periods of remission and usually lasts for 10-15 years. The second phase sees progression of the disease, leading to chronic disability. Currently, there are no drugs available that effectively interfere with the progression of MS. The importance of the results of the current study lies in the identification of MCAM as a valid therapeutic target for MS.
Normally the blood-brain barrier prevents migration of T lymphocytes, which are the primary cells involved in adaptive immune responses, into the CNS. However, in MS this protection is compromised and both CD4 and CD8 T lymphocytes can cross the blood-brain barrier and launch an immune attack on the myelin sheath in the brain which protects neurons. This in turn causes compromised nerve impulse transmission and laying down of plaques in the brain. In the current study, the research team used a comprehensive combination of ex vivo, in vitro, in situ and in vivo approaches in both human and mouse, including healthy controls, MS subjects and experimental autoimmune encephalomyelitis (EAE) animals, which act as an animal model of MS, to dissect the role of MCAM.
The results of the study showed that MCAM is expressed by pathogenic human effector CD8+ T lymphocytes and its levels were strikingly increased during MS relapses. They also showed that the MCAM+ CD8 T lymphocytes expressed higher levels of pro-inflammatory mediators, including IL-17, IFN-γ, GM-CSF and TNF, than CD8 T lymphocytes that did not express MCAM and that they more effectively killed oligodendrocytes. Importantly, blocking MCAM blockade restricted CD8+ T lymphocytes migration across an in vitro endothelial cell human blood-brain barrier model, and blocking or depleting MCAM in vivo in EAE mice reduced chronic neurological deficits in this MS model. Dr Prat commented: "Our studies have shown that MCAM is necessary for the migration of CD4 and CD8 across the blood-brain barrier. If we block the interaction of MCAM with the protein to which it normally binds, we decrease the disease's activity,"
Independently, Prothena have developed an antibody called PRX003, which is designed to inhibit MCAM function and hence prevent migration of destructive lymphocytes into tissue. Prothena plans initiation of clinical trials of PRX003 in healthy volunteers by the end of June, and if all goes well by 2016 they are anticipating a study in psoriasis patients. The results of the current study suggest that anti-MCAM antibodies such as PRX003 may have applications beyond psoriasis, in treatment of neurodegenerative diseases such as multiple sclerosis. Dr Prat said: "We believe we have identified the first therapy that will impact the quality of life of people with multiple sclerosis by significantly reducing the disability and the disease's progression."
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Science news reference:
MCAM+ CD8 T lymphocytes mediate CNS inflammation. Larochelle C, Lécuyer M-A, Alvarez JI, Charabati M, Saint-Laurent O, Ghannam S, Kebir H, Flanagan K, Yednock T, Duquette P, Arbour N, Prat A. Annals of Neurology (2015) DOI: 10.1002/ana.24415
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