Tuesday, 18 September 2012

Research: Another Tysabri-like drug for the future

Larochelle C, Cayrol R, Kebir H, Alvarez JI, Lécuyer MA, Ifergan I, Viel E, Bourbonnière L, Beauseigle D, Terouz S, Hachehouche L, Gendron S, Poirier J, Jobin C, Duquette P, Flanagan K, Yednock T, Arbour N, Prat A. Melanoma cell adhesion molecule identifies encephalitogenic T lymphocytes and promotes their recruitment to the central nervous system. Brain. 2012 Sep 13. [Epub ahead of print]

In multiple sclerosis, encephalitogenic CD4(+) lymphocytes require adhesion molecules to accumulate into central nervous system inflammatory lesions. Using proteomic techniques, we identified expression of melanoma cell adhesion molecule (MCAM) on a subset of human effector memory CD4(+) lymphocytes and on human blood-brain barrier endothelium. Herein, we demonstrate that MCAM is a stable surface marker that refines the identification of interleukin 17(+), interleukin 22(+), RAR-related orphan receptor γ and interleukin 23 receptor(+) cells within the CD161(+)CCR6(+) subset of memory CD4(+) lymphocytes. We also show that MCAM(+) lymphocytes express significantly more granulocyte/macrophage colony stimulating factor and granzyme B than MCAM(-) lymphocytes. Furthermore, the proportion of MCAM(+) CD4(+) lymphocytes is significantly increased in the blood and in the central nervous system of patients with multiple sclerosis and experimental autoimmune encephalomyelitis animals compared with healthy controls or other neurological diseases, and MCAM expression is upregulated at the blood-brain barrier within inflammatory lesions. Moreover, blockade of MCAM or depletion of MCAM(+) CD4(+) T lymphocytes both restrict the migration of T(H)17 lymphocytes across blood-brain barrier endothelial cells and decrease the severity of experimental autoimmune encephalomyelitis. Our findings indicate that MCAM could serve as a potential biomarker for multiple sclerosis and represents a valuable target for the treatment of neuroinflammatory conditions. 

Tysari was the brain child of a guy called Ted Yednock and now he is on the hunt for the next generation. Tysabri blocks very later antigen four of alpha4 beta one integrinor CD49d.. This is used for white blood cells to get into the brain. It is also used by cells that can destroy viruses in the brain and so PML is a risk from tysabri.

They have found another target called melanoma cell adhession molecule CD146), obviously because it was first identified when examining melanoma migration. This found on a subset of T cells and on endothelial cells. Here they show that antibodies to MCAM can block cells getting into the brain of animals with an MS-like disease and it may be present on disease causing cells. It has already been reported that MCAM is involved in the initial steps of lymphocyte endothelium interaction. By promoting the rolling on the inflammation marker VCAM-1, which is the receptor for CD49d via microvilli induction and displaying adhesion receptor activity involving possible MCAM-l-MCAM-l (white blood cell-to blood cell) interactions, MCAM might be involved in the recruitment of activated T cells to inflammation sites. This study shows it is and can be another avenue for treatment and maybe it is more selective so as to reduce the risks of PML. This is a long way off beoming a new treatment for MS.

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