Peripheral accumulation of newly produced T and B lymphocytes in natalizumab-treated multiple sclerosis patients

Abstract

The anti-α4 monoclonal antibody natalizumab inhibits lymphocyte extravasation into the central nervous system and increases peripheral T and B lymphocytes in multiple sclerosis patients. To investigate whether the lymphocyte accumulation was due to a higher lymphocyte production, an altered homeostasis, or a differential transmigration of lymphocyte subsets through endothelia, T-cell receptor excision circles and kappa-deleting recombination excision circles were quantified before and after treatment, T-cell receptor repertoire was analyzed by spectratyping, and T-and B-lymphocyte subset migration was studied using transwell coated with vascular and lymphatic endothelial cells. We found that the number of newly produced T and B lymphocytes is increased because of a high release and of a low propensity of naïve subsets to migrate across endothelial cells. In some patients this resulted in an enlargement of T-cell heterogeneity. Because new lymphocyte production ensures the integrity of immune surveillance, its quantification could be used to monitor natalizumab therapy safety.

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

“…This discrepancy could be explained by the fact that repeated comparisons, instead of a single comparison, compared to the baseline value were made during some years of therapy. The origin of B cells is still a matter of debate as to whether they originate from BM cells [7] or peripheral cells [14]. However, considering the scarcity of leucocytes compared to periphery cells in the CNS and the minor contribution of memory and marginal zone-like B cells in composing the lymphocyte pool, it is unlikely that the reduced migration of leucocytes into the CNS and the decreased retention of specific B cell subsets in the spleen can quantitatively affect peripheral lymphocyte count or fully explain the increase of lymphocytes observed during natalizumab therapy.…”

“…It prevents the binding between VLA-4 and the vascular endothelium cell adhesion molecule 1 (VCAM-1) which, over time, decreases α4 expression [2]. The result consists of a reduced extravasation of inflammatory immune cells across the blood-brain barrier into the central nervous system (CNS), consequently increasing the number of immune cells in the peripheral blood [3][4][5][6][7]. However, natalizumab treatment can affect lymphocyte subsets in different ways, as the α4β1 integrins are expressed differently on lymphocyte subtypes, with higher levels on B than on T cells, on CD8…”

Newly produced T and B lymphocytes and T-cell receptor repertoire diversity are reduced in peripheral blood of fingolimod-treated multiple sclerosis patients

“…16 RTE and naive CD8 + T cells, as well as immature and naive B cells, were identified using a FACSCanto II cytometer and results were analyzed with FACSDiva software (BD Biosciences), as previously described. 17 Data were reported as percentage and as absolute count per µl of blood.…”

Immunomonitoring Lymphocyte Subpopulations in Multiple Sclerosis Patients

“…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).…”