Inhibition of the Progression of Multiple Sclerosis by Linomide Is Associated with Upregulation of CD4+/CD45RA+Cells and Downregulation of CD4+/CD45RO+Cells

Abstract

In a recent double-blind, phase II study, conducted in our department, we showed that Linomide-treated MS patients had significantly less active lesions (in serial monthly MRI tests) and a tendency for clinical stabilization. Here we present the immunological evaluation of the patients who participated in this study and propose a novel mechanism by which Linomide downregulates autoreactivity. Peripheral blood leukocytes (PBLs), serum, and CSF samples were obtained at two to four time points over the 6 months of the trial. Flow cytometric analysis (FACS) of the CD5/CD19, CD4/CD8, CD14/CD3, CD16/CD3, CD45RA/CD4, and CD45RO/CD4 surface markers on PBLs was performed and the levels of the IL-1β, IL-2, IL-4, IL-6, IL-10, TNF-α, IFN-γ, and IL-2R were also examined. White blood counts of Linomide-treated patients were consistently elevated throughout the treatment period (P= 0.002–0.04). Cytokines levels in serum and CSF were highly fluctuating and we could not detect any clear trend as a result of Linomide treatment. FACS analysis showed that Linomide treatment significantly increased the percentage of the CD4+/CD45RA+cells (from 35.5% at baseline to 42.3% at week 24;P= 0.02), and decreased CD4+/CD45RO+lymphocytes (62.6% at baseline vs 53.7% at week 24,P= 0.02). Linomide also induced a transient increase in the NK-cells, the NK 1.1 cells, and the CD5 B-cells (P= 0.02). Upregulation of naive CD45RA T-lymphocytes and parallel downregulation of memory CD45RO cells seems to be one of the main mechanisms by which Linomide inhibits MS activity and may represent an alternative immunomodulating approach for the treatment of MS and autoimmunity in general.