title: Basis for fluctuations in lymphocyte counts in fingolimod-treated patients with multiple sclerosis.
abstract: OBJECTIVE
  To determine the range of fluctuation in total lymphocyte counts (TLCs) in peripheral blood over a 4- to 7-year period in patients with MS receiving fingolimod (FTY720) and the relation between TLCs and T-cell subsets (CD4+, CD8+, CCR7+/-) that are differentially regulated in the lymph nodes by fingolimod.
  
  
  METHODS
  TLCs were measured every 3 months in patients (n = 23) receiving fingolimod for 4 to 7 years. T-cell subset (CD4+, CD8+, and CCR7+/-) analyses were performed on whole-blood samples and/or freshly isolated or cryopreserved mononuclear cells.
  
  
  RESULTS
  All serially studied patients had mean TLCs <0.6 × 10(9) lymphocytes/L. In 30% of patients, 20% to 40% of TLCs were >0.6 × 10(9) lymphocytes/L vs mean 4.0% for "nonfluctuator" patients. Cross-sectional analysis indicated that TLCs of 0.2-0.6 × 10(9) lymphocytes/L correlated with numbers of CD8+ effector (CCR7-) cells. For patients discontinuing therapy, TLCs between 0.6 and 1.0 × 10(9) lymphocytes/L were associated with a relative increase of CD4 T cells and reappearance of CCR7+ (CD4+ and CD8+) T cells. Analysis of cryopreserved mononuclear cell samples from patients receiving therapy with TLCs >0.6 × 10(9) lymphocytes/L indicated no differences in total CD4 or CD8+ T cells but increased proportion of CD4+CCR7+ T cells compared to samples with TLCs <0.6 × 10(9) lymphocytes/L.
  
  
  CONCLUSIONS
  Fluctuations of TLCs within 0.2-0.6 × 10(9) lymphocytes/L in patients receiving fingolimod reflect changes in total CCR7-CD8+ effector cells, a population less regulated by this agent. Although less apparent than for patients discontinuing therapy, cells expected to be sequestered by this therapy may begin to re-emerge when TLC values are >0.6 × 10(9) lymphocytes/L.
authors.affiliation: From the Neuroimmunology Unit, Montreal Neurological Institute, McGill University, Canada.
authors.forename: David
authors.initials: D
authors.lastname: Henault
authors.forename: Lorna
authors.initials: L
authors.lastname: Galleguillos
authors.forename: Craig
authors.initials: C
authors.lastname: Moore
authors.forename: Trina
authors.initials: T
authors.lastname: Johnson
authors.forename: Amit
authors.initials: A
authors.lastname: Bar-Or
authors.forename: Jack
authors.initials: J
authors.lastname: Antel
mesh_terms: D000328:Adult; D002452:Cell Count; D016207:Cytokines / Q000378:metabolism; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D008137:Longitudinal Studies; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000473:pathology*; D011409:Propylene Glycols / Q000627:therapeutic use*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000145:classification / Q000187:drug effects / Q000473:pathology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D011409:Propylene Glycols; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine