期刊
JOURNAL OF EXPERIMENTAL MEDICINE
卷 211, 期 9, 页码 1833-1846出版社
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20140540
关键词
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资金
- Deutsche Forschungsgesellschaft (DFG) [CRC128/B1, CRC128/Z2, CRC128/Z1, ZA428/6-1, SFB 1009/A3, SFB 1009/A5]
- DFG EXC 1003 Cells in Motion - Cluster of Excellence (Project B, Cells in barriers), Munster, Germany [DFG_GR3946_1_1]
- EU (BEST-MS, FP7) [305477]
- German Ministry for Health and Education German competence network of MS (KKNMS), project B1 Pharmacovigilance Study Natalizumab
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(+)/T(H)17 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 T(H)17 cells to migrate over the blood-brain barrier.
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