Genomic Effects of IFN- in Multiple Sclerosis Patients

The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-1a treatment regimen in multiple sclerosis patients and to examine the molecular mechanisms potentially capable of causing heterogeneity in response to therapy. In this open-label pharmacodynamic study design, peripheral blood was obtained from eight relapsingremitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 g of IFN-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN-1a treatment resulted in selective, time-dependent effects on multiple genes. The mRNAs for genes implicated in the anti-viral response, e.g., double-stranded RNA-dependent protein kinase, myxovirus resistance proteins 1 and 2, and guanylate binding proteins 1 and 2 were rapidly induced within 1–4 h of IFNtreatment. The mRNAs for several genes involved in IFNsignaling, such as IFN/ receptor-2 and Stat1, were also increased. The mRNAs for lymphocyte activation markers, such as IFN-induced transmembrane protein 1 (9–27), IFN-induced transmembrane protein 2 (1–8D), 2-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFNtreatment induces specific and time-dependent changes in multiple mRNAs in lymphocytes of multiple sclerosis patients that could provide a framework for rapid monitoring of the response to therapy. The Journal of Immunology, 2003, 171: 2694–2702.