Saturday, 23 August 2014

A way in for white cells on trysabri

VLA-4 blockade promotes differential routes into human CNS involving PSGL-1 rolling of T cells and MCAM-adhesion of TH17 cells.Schneider-Hohendorf T, Rossaint J, Mohan H, Böning D, Breuer J, Kuhlmann T, Gross CC, Flanagan K, Sorokin L, Vestweber D, Zarbock A, Schwab N, Wiendl H.J Exp Med. 2014 Aug 18. pii: jem.20140540. [Epub ahead of print]

The focus of this study is the characterization of human T cell blood-brain barrier migration and corresponding molecular trafficking signatures. We examined peripheral blood and cerebrospinal fluid immune cells from patients under long-term anti-very late antigen-4 (VLA-4)/natalizumab therapy (LTNT) and from CNS specimens. LTNT patients' cerebrospinal fluid T cells exhibited healthy central-/effector-memory ratios, but lacked CD49d and showed enhanced myeloma cell adhesion molecule (MCAM) expression. LTNT led to an increase of PSGL-1 expression on peripheral T cells. Although vascular cell adhesion molecule-1 (VLA-4 receptor) was expressed at all CNS barriers, P-selectin (PSGL-1-receptor) was mainly detected at the choroid plexus. Accordingly, in vitro experiments under physiological flow conditions using primary human endothelial cells and LTNT patients' T cells showed increased PSGL-1-mediated rolling and residual adhesion, even under VLA-4 blockade. Adhesion of MCAM+/TH17 cells was not affected by VLA-4 blocking alone, but was abrogated when both VLA-4 and MCAM were inhibited. Consistent with these data, MCAM+ cells were detected in white matter lesions, and in gray matter of multiple sclerosis patients. Our data indicate that lymphocyte trafficking into the CNS under VLA-4 blockade can occur by using the alternative adhesion molecules, PSGL-1 and MCAM, the latter representing an exclusive pathway for TH17 cells to migrate over the blood-brain barrier


Tysabri binds to and blocks the VLA-4 (CD49d) of alpha4, beta 1 interin on white blood cells which docks with vascular cell adhesion molecule-1 (VCAM-1/CD106) on blood vessels and can stop white blood cellsfrom getting into the brain and causing lesions. However, this study shows there are still ways in for white cells. Although CD49d is blocked white cells upregulate PSGL-1 (CD162) and binding by this to MCAM was not affected for some Th17 cells.
So as tysabri inhibits relapsing MS are we to concludethat Th17 cells are unimportant, or maybe there is not level of immune surveillence of the brain under tysabri.

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