Genomic Effects of IFN-β in Multiple Sclerosis Patients

Abstract

The purpose of this report was to characterize the dynamics of the gene expression cascades induced by an IFN-β-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 relapsing-remitting multiple sclerosis patients just before and at 1, 2, 4, 8, 24, 48, 120, and 168 h after i.m. injection of 30 μg of IFN-β-1a. The total RNA was isolated from monocyte-depleted PBL and analyzed using cDNA microarrays containing probes for >4000 known genes. IFN-β-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 IFN-β treatment. The mRNAs for several genes involved in IFN-β signaling, such as IFN-α/β 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), β2-microglobulin, and CD69, were also increased in a time-dependent manner. The findings demonstrate that IFN-β treatment 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.

A subtype of multiple sclerosis defined by an activated immune defense program

“…Not so surprisingly, several reports have demonstrated an induction of the type-I IFN response program in patients treated with IFN-b . 40,41 As anticipated, the one patient receiving IFN-b therapy clustered together with the RRMS high patients and showed an upregulation of IFN-induced genes. Although transcription-based prediction of IFN-b therapy has been studied, 42,43 future research in a large cohort of patients is needed to sort out whether the absence or presence of a type-I IFN response in the PB of patients with RRMS is a prognostic factor for successful treatment with IFN-b.…”

IFN-β1a Inhibits the Secretion of Th17-Polarizing Cytokines in Human Dendritic Cells via TLR7 Up-Regulation

“…IFN-␤1a's reported mechanisms of action include inhibition of MHC class II expression on monocytes and microglia, suppression of T cell proliferation, regulation of IL-12/IL-10 cytokine transcription, and inhibition of inflammatory cell migration into the CNS via interference with VLA-4-mediated cell adhesion and matrix metalloproteinase 9 activity (3). However, IFN-␤'s effects are complex and cellular responses to IFN-␤ involve Ͼ500 genes (4), suggesting that some of the relevant mechanisms of action may still not be identified. Although IFN-␤ is secreted during the antiviral innate immune response, the physiological role of endogenous type I IFNs in the regulation of the adaptive immune response is poorly understood.…”

Neutralizing antibodies in interferon beta treated patients with multiple sclerosis: knowing what to do now

“…Recently it was demonstrated that measuring the mRNA response of the IFNb-induced antiviral MxA protein ex vivo by quantitative PCR yields a good correlate of the bioavailability of IFNb in a given subject [16,20]. However, since there are inter-individually different response curves of the MxA mRNA expression, a small proportion of patients may be classified false-positively [21][22][23]. To minimize this potential error it would be ideal to compare individual MxA mRNA responses on IFNb therapy with the respective responses at treatment initiation of the same individual [24].…”