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.
Lymphocytes (blue)and red blood cells (red) in the microscope
The mechanism that causes the increase in the number of lymphocytes in the peripheral blood of MSers on natalizumab (Tysabri) was studied with a in vitro system that mimics blood vessels. So the lymphocytes are not the ones that would have gone to the brain and spinal cord... but they are new lymphocytes that cannot cross the walls of blood vessels as easily. So far, there are no safety concerns with this raised number of lymphocytes.