Cell Type-Specific Gene Expression Changes in the Blood of Multiple Sclerosis Patients in the Early Phase of Interferon-beta Treatment

OBJECTIVE: We analyzed in parallel the gene expression profiles of 5 blood cell populations before and during treatment with subcutaneous interferon-beta (IFN-beta) to obtain deeper insights into the drug9s mechanisms of action and to confirm and refine potential biomarkers for therapy monitoring and disease prognosis. BACKGROUND: Previous studies have identified more than a hundred genes to be modulated in expression during IFN-beta treatment. Most of these studies used just whole blood or peripheral blood mononuclear cells (PBMC), which are a mixture of different cell populations. Cell type-specific investigations could yield more discriminative biomarkers of the biological and clinical response to METHODS: With informed consent, blood samples were collected from 32 patients with relapsing-remitting multiple sclerosis (RRMS) or clinically isolated syndrome (CIS) before IFN-beta treatment initiation as well as after 2 days and 1 month. T helper cells, cytotoxic T-cells, monocytes, B-cells and PBMC were separated. The OpenArray real-time PCR platform was used for high-throughput gene expression analysis of 106 transcripts. Differentially expressed genes were determined by fold-change and t-test. RESULTS: About 42300 real-time PCR reactions passed the quality control. Approximately half of the IFN-beta-responsive genes seen after 1 month were significantly changed in expression already after the first injection. The IFN-beta signature was most prominent in monocytes. However, IFI44, MX1 and XAF1 were consistently expressed at higher mRNA levels in all 5 cell populations. Differences in baseline expression distinguished patients with continued disease activity in the clinical follow-up. CONCLUSIONS: Treatment with IFN-beta provokes different gene regulatory effects in different cell types of the blood. IFN-beta-responsive genes were typically increased in expression in monocytes after 1 month of therapy. Gene expression differences over time and between patients were usually greater in individual immune cell types than in PBMC, which allows to derive improved molecular biomarkers. Study supported by: Bayer HealthCare Disclosure: Dr. Hecker has received personal compensation for activities with Bayer HealthCare, Biogen, Novartis and Teva as speaker. Dr. Fitzner has nothing to disclose. Dr. Koczan has nothing to disclose. Dr. Schroeder has nothing to disclose. Dr. Thiesen has nothing to disclose. Dr. Zettl has received personal compensation for activities with Bayer HealthCare, Biogen, Merck Serono, Novartis, Sanofi, Almirall, and Teva.