Long-term follow-up of peripheral lymphocyte subsets in a cohort of multiple sclerosis patients treated with natalizumab

Abstract

SummaryNatalizumab, an anti-alpha4 integrin monoclonal antibody inhibiting the adhesion of lymphocytes to the endothelium, is a widely accepted drug treatment for relapsing-remitting multiple sclerosis (RRMS). A peripheral increase of T and B lymphocytes has already been observed as an early treatment effect. This retrospective observational study was aimed to evaluate the peripheral lymphocyte subsets during a long-term treatment follow-up. We included 23 RRMS patients treated with natalizumab for at least 24-48 months who had pretreatment lymphocyte evaluation. Baseline values of lymphocyte subsets and CD4/CD8 ratio did not differ significantly from the 23 matched healthy subjects. The periodic (every 3-6 months) assessment of immune cell subsets was performed by flow cytometry on peripheral blood collected before drug injection. Therapy with natalizumab was confirmed to be effective during the observational period. For all patients, the increase in lymphocytes during natalizumab therapy compared to baseline at every assessment was significantly higher compared to that of overall white blood cells (2·1-and 1·3-fold, respectively, P < 0·0001). Both T cell subsets were proportionally modified and the CD4/CD8 ratio did not change significantly, while B cells increased significantly compared to T and NK cells (3·2-, 1·88-and 1·92-fold, respectively, P < 0·0001). These changes remained constant throughout the 25-48-month period of therapy. In conclusion, effective natalizumab treatment of RRMS patients was associated with the persistence of its biological effects through a stable increase of peripheral lymphocytes, mainly B cells, and an unchanged proportion of T cell subsets in long-term follow-up.

Quantification of γδ T cells and HLA-DR+ NK cells does not predict emergence of new contrast enhancing lesions in MS patients suspending natalizumab treatment

“…This observation is consistent with previous reports that NTZ treatment leads to an overall increase in T cell populations and noticeable changes in the cytotoxic CD3 - CD56 dim NK cell subset [14–16]. Similar to our study, the proportion of HLA-DR + NK cells in the total NK cell population was unchanged [15].…”

Effect of Multiple Sclerosis Disease-Modifying Therapies on B Cells and Humoral Immunity

“…29 Natalizumab treatment frequently leads to a corresponding peripheral leukocytosis, with circulating B lymphocytes being disproportionately elevated relative to other cell types. 30,31 This expansion is partly owing to an influx of newly produced cells; circulating B-cell precursors are increased in treated patients. 31,32 B-cell homeostasis is also affected.…”

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

“…The main side effect of natalizumab is the risk of developing PML caused by JC virus infection, which is associated with high mortality. As natalizumab blocks the transmigration of leukocytes through the BBB, in the peripheral blood of MS patients under treatment with natalizumab, there is an increase in the absolute numbers of B, T CD4 + , T CD8 + (without alterations in CD4/CD8 ratio), and NK cells (88)(89)(90). The effect of natalizumab on lymphocyte subpopulations is not fully defined, although it has been described that memory T-cells would be increased in peripheral blood and would induce changes in memory B-cells (90)(91)(92).…”

“…As natalizumab blocks the transmigration of leukocytes through the BBB, in the peripheral blood of MS patients under treatment with natalizumab, there is an increase in the absolute numbers of B, T CD4 + , T CD8 + (without alterations in CD4/CD8 ratio), and NK cells (88)(89)(90). The effect of natalizumab on lymphocyte subpopulations is not fully defined, although it has been described that memory T-cells would be increased in peripheral blood and would induce changes in memory B-cells (90)(91)(92). Moreover, natalizumab treatment interferes with the mechanisms of bone marrow egress of hematopoietic stem cells, inducing an increase of CD34 + cells in peripheral blood, specifically lymphoid progenitors, transitional B-cells, and RTEs (17,91,(93)(94)(95)(96)(97).…”