title: Altered CD4+/CD8+ T-cell ratios in cerebrospinal fluid of natalizumab-treated patients with multiple sclerosis.
abstract: BACKGROUND
  Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an alpha4beta(1) integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.
  
  
  OBJECTIVE
  To test the effect of natalizumab treatment on the CD4(+)/CD8(+) T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.
  
  
  METHODS
  Prospective longitudinal study.
  
  
  METHODS
  Academic and private multiple sclerosis centers.
  
  
  METHODS
  Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus-infected patients.
  
  
  METHODS
  CD4(+) and CD8(+) T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound alpha4 integrin on peripheral blood CD4(+) and CD8(+) T cells was analyzed before and after natalizumab therapy.
  
  
  RESULTS
  Natalizumab therapy decreased the CSF CD4(+)/CD8(+) ratio of patients with MS to levels similar to those of human immunodeficiency virus-infected patients. CD4(+)/CD8(+) ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4(+)/CD8(+) ratios normalized. The expression of unbound alpha4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4(+) vs CD8(+) T cells.
  
  
  CONCLUSIONS
  Natalizumab treatment alters the CSF CD4(+)/CD8(+) ratio. Lower expression of unbound alpha4 integrin on CD4(+) T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.
authors.affiliation: Department of Neurology, University of Texas Southwestern Medical Center at Dallas, USA.
authors.forename: Olaf
authors.initials: O
authors.lastname: Stüve
authors.forename: Christina M
authors.initials: CM
authors.lastname: Marra
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.forename: Masaaki
authors.initials: M
authors.lastname: Niino
authors.forename: Petra D
authors.initials: PD
authors.lastname: Cravens
authors.forename: Sabine
authors.initials: S
authors.lastname: Cepok
authors.forename: Elliot M
authors.initials: EM
authors.lastname: Frohman
authors.forename: J Theodore
authors.initials: JT
authors.lastname: Phillips
authors.forename: Gabriele
authors.initials: G
authors.lastname: Arendt
authors.forename: Keith R
authors.initials: KR
authors.lastname: Jerome
authors.forename: Linda
authors.initials: L
authors.lastname: Cook
authors.forename: Francois
authors.initials: F
authors.lastname: Grand'Maison
authors.forename: Bernhard
authors.initials: B
authors.lastname: Hemmer
authors.forename: Nancy L
authors.initials: NL
authors.lastname: Monson
authors.forename: Michael K
authors.initials: MK
authors.lastname: Racke
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects*; D061067:Antibodies, Monoclonal, Humanized; D018791:CD4 Lymphocyte Count; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D015331:Cohort Studies; D005260:Female; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy / Q000009:adverse effects*; D039041:Integrin alpha4beta1 / Q000187:drug effects / Q000378:metabolism; D007968:Leukoencephalopathy, Progressive Multifocal / Q000139:chemically induced / Q000276:immunology; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000134:cerebrospinal fluid / Q000188:drug therapy* / Q000276:immunology*; D000069442:Natalizumab; D011446:Prospective Studies
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D039041:Integrin alpha4beta1; D000069442:Natalizumab