INHIBITION OF THE PROGRESSION OF MULTIPLE-SCLEROSIS BY LINOMIDE IS ASSOCIATED WITH UP-REGULATION OF CD4(+) CD45RA(+) CELLS AND DOWN-REGULATION OF CD4(+)/CD45RO(+) CELLS/

In a recent double-blind, phase II study, conducted in our department, we showed that Linomide-treated MS patients had significantly less ac tive lesions (in serial monthly MRI tests) and a tendency for clinical stabilization. Here we present the immunological evaluation of the pa tients who participated in this study and propose a novel mechanism by which Linomide downregulates autoreactivity. Peripheral blood leukocy tes (PBLs), serum, and CSF samples were obtained at two to four time p oints 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/C D4 surface markers on PBLs was performed and the levels of the IL-1 be ta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, IFN-gamma, and IL-2R were also examined. White blood counts of Linomide-treated patients were consis tently elevated throughout the treatment period (P = 0.002-0.04). Cyto kines levels in serum and CSF were highly fluctuating and we could not detect any clear trend as a result of Linomide treatment. BAGS analys is showed that Linomide treatment significantly increased the percenta ge of the CD4(+)/CD45RA(+) cells (from 35.5% at baseline to 42.3% at w eek 24; P = 0.02), and decreased CD4(+)/CD45RO(+) lymphocytes (62.6% a t baseline vs 53.7% at week 24, P = 0.02). Linomide also induced a tra nsient 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 d ownregulation of memory CD45RO cells seems to be one of the main mecha nisms by which Linomide inhibits MS activity and may represent an alte rnative immunomodulating approach for the treatment of MS and autoimmu nity in general. (C) 1997 Academic Press.