Basis for fluctuations in lymphocyte counts in fingolimod-treated patients with multiple sclerosis

Abstract

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. 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. 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. 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.