title: High interindividual variability in the CD4/CD8 T cell ratio and natalizumab concentration levels in the cerebrospinal fluid of patients with multiple sclerosis.
abstract: Strongly decreased leucocyte counts and a reduced CD4/CD8 T cell ratio in the cerebrospinal fluid (CSF) of natalizumab (NZB)-treated multiple sclerosis (MS) patients may have implications on central nervous (CNS) immune surveillance. With regard to NZB-associated progressive multi-focal leucoencephalopathy, we aimed at delineating a relationship between free NZB, cell-bound NZB, adhesion molecule (AM) expression and the treatment-associated shift in the CSF T cell ratio. Peripheral blood (PB) and CSF T cells from 15 NZB-treated MS patients, and CSF T cells from 10 patients with non-inflammatory neurological diseases and five newly diagnosed MS patients were studied. Intercellular adhesion molecule-1 (ICAM-1), leucocyte function antigen-1 (LFA-1), very late activation antigen-4 (VLA-4), NZB saturation levels, and T cell ratios were analysed by flow cytometry. NZB concentrations were measured by enzyme-linked immunosorbent assay (ELISA). Lower NZB saturation levels (P<0.02) and a higher surface expression of ICAM-1 and LFA-1 (P<0.001) were observed on CSF CD8 T cells. CSF T cell ratios (0.3-2.1) and NZB concentrations (0.01-0.42 µg/ml) showed a pronounced interindividual variance. A correlation between free NZB, cell-bound NZB or AM expression levels and the CSF T cell ratio was not found. Extremely low NZB concentrations and a normalized CSF T cell ratio were observed in one case. The differential NZB saturation and AM expression of CSF CD8 T cells may contribute to their relative enrichment in the CSF. The reduced CSF T cell ratio appeared sensitive to steady-state NZB levels, as normalization occurred quickly. The latter may be important concerning a fast reconstitution of CNS immune surveillance.
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: A
authors.initials: A
authors.lastname: Harrer
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: G
authors.initials: G
authors.lastname: Pilz
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: P
authors.initials: P
authors.lastname: Wipfler
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: K
authors.initials: K
authors.lastname: Oppermann
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.|Department of Neurology, Klinikum rechts der Isar, Technische Universät München, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Sellner
authors.affiliation: Research Office (Biostatistics), Paracelsus Medical University, Salzburg, Austria.
authors.forename: W
authors.initials: W
authors.lastname: Hitzl
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Haschke-Becher
authors.affiliation: Department of Laboratory Medicine, Paracelsus Medical University, Salzburg, Austria.
authors.forename: S
authors.initials: S
authors.lastname: Afazel
authors.affiliation: Department of Immunopathology, Sanquin Research and Academic Medical Centre, Amsterdam, the Netherlands.
authors.forename: T
authors.initials: T
authors.lastname: Rispens
authors.affiliation: Laboratory for Monoclonal Therapeutics, Sanquin Diagnostics, Amsterdam, the Netherlands.
authors.forename: D
authors.initials: D
authors.lastname: van der Kleij
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.
authors.forename: E
authors.initials: E
authors.lastname: Trinka
authors.affiliation: Department of Neurology, Paracelsus Medical University, Salzburg, Austria.|Department of Neurology, A.ö. Krankenhaus Zell am See, Teaching Hospital of the Paracelsus Medical University Salzburg, Zell am See, Austria.
authors.forename: J
authors.initials: J
authors.lastname: Kraus
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D016516:CD4-CD8 Ratio; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002555:Cerebrospinal Fluid / Q000166:cytology*; D016903:Drug Monitoring; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology* / Q000378:metabolism; D000069442:Natalizumab; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015815:Cell Adhesion Molecules; D016169:Lymphocyte Function-Associated Antigen-1; D000069442:Natalizumab; D018799:Intercellular Adhesion Molecule-1
keywords: CD4/CD8; T cell ratio; adhesion molecules; cerebrospinal fluid; multiple sclerosis; natalizumab