title: Effect of natalizumab on circulating CD4+ T-cells in multiple sclerosis.
abstract: In multiple sclerosis (MS), treatment with the monoclonal antibody natalizumab effectively reduces the formation of acute lesions in the central nervous system (CNS). Natalizumab binds the integrin very late antigen (VLA)-4, expressed on the surface of immune cells, and inhibits VLA-4 dependent transmigration of circulating immune-cells across the vascular endothelium into the CNS. Recent studies suggested that natalizumab treated MS patients have an increased T-cell pool in the blood compartment which may be selectively enriched in activated T-cells. Proposed causes are sequestration of activated T-cells due to reduced extravasation of activated and pro-inflammatory T-cells or due to induction of VLA-4 mediated co-stimulatory signals by natalizumab. In this study we examined how natalizumab treatment altered the distribution of effector and memory T-cell subsets in the blood compartment and if T-cells in general or myelin-reactive T-cells in particular showed signs of increased immune activation. Furthermore we examined the effects of natalizumab on CD4(+) T-cell responses to myelin in vitro. Natalizumab-treated MS patients had significantly increased numbers of effector-memory T-cells in the blood. In T-cells from natalizumab-treated MS patients, the expression of TNF-α mRNA was increased whereas the expression of fourteen other effector cytokines or transcription factors was unchanged. Natalizumab-treated MS patients had significantly decreased expression of the co-stimulatory molecule CD134 on CD4(+)CD26(HIGH) T-cells, in blood, and natalizumab decreased the expression of CD134 on MBP-reactive CD26(HIGH)CD4(+) T-cells in vitro. Otherwise CD4(+) T-cells from natalizumab-treated and untreated MS patients showed similar responses to MBP. In conclusion natalizumab treatment selectively increased the effector memory T-cell pool but not the activation state of T-cells in the blood compartment. Myelin-reactive T-cells were not selectively increased in natalizumab treated MS.
authors.affiliation: Danish Multiple Sclerosis Center, Department of Neurology, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. boernsen@gmail.com
authors.forename: Lars
authors.initials: L
authors.lastname: Börnsen
authors.forename: Jeppe Romme
authors.initials: JR
authors.lastname: Christensen
authors.forename: Rikke
authors.initials: R
authors.lastname: Ratzer
authors.forename: Annette Bang
authors.initials: AB
authors.lastname: Oturai
authors.forename: Per Soelberg
authors.initials: PS
authors.lastname: Sørensen
authors.forename: Helle Bach
authors.initials: HB
authors.lastname: Søndergaard
authors.forename: Finn
authors.initials: F
authors.lastname: Sellebjerg
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use*; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016022:Case-Control Studies; D002464:Cell Migration Inhibition / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D039041:Integrin alpha4beta1 / Q000235:genetics / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D004676:Myelin Basic Protein / Q000235:genetics / Q000276:immunology; D000069442:Natalizumab; D053262:Receptors, OX40 / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D004676:Myelin Basic Protein; D000069442:Natalizumab; D053262:Receptors, OX40; D014409:Tumor Necrosis Factor-alpha