Abstract
BackgroundMultiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNß in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNß therapy.MethodologyLarge scale gene expression profiling was performed on peripheral blood of 16 RRMS patients at baseline and one month after the start of IFNß therapy. Differential gene expression was analyzed by Significance Analysis of Microarrays. Subsequent expression analyses on specific genes were performed after three and six months of treatment. Peripheral blood mononuclear cells (PBMC) were isolated and stimulated in vitro with IFNß. Genes of interest were measured and validated by quantitative realtime PCR. An independent group of 30 RRMS patients was used for validation.Principal FindingsPharmacogenomics revealed a marked variation in the pharmacological response to IFNß between patients. A total of 126 genes were upregulated in a subset of patients whereas in other patients these genes were downregulated or unchanged after one month of IFNß therapy. Most interestingly, we observed that the extent of the pharmacological response correlates negatively with the baseline expression of a specific set of 15 IFN response genes (R = −0.7208; p = 0.0016). The negative correlation was maintained after three (R = −0.7363; p = 0.0027) and six (R = −0.8154; p = 0.0004) months of treatment, as determined by gene expression levels of the most significant correlating gene. Similar results were obtained in an independent group of patients (n = 30; R = −0.4719; p = 0.0085). Moreover, the ex vivo results could be confirmed by in vitro stimulation of purified PBMCs at baseline with IFNß indicating that differential responsiveness to IFNß is an intrinsic feature of peripheral blood cells at baseline.ConclusionThese data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNß.
Highlights
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction
The ex vivo results could be confirmed by in vitro stimulation of purified Peripheral blood mononuclear cells (PBMC) at baseline with IFNß indicating that differential responsiveness to IFNß is an intrinsic feature of peripheral blood cells at baseline. These data imply that the expression levels of IFN response genes in the peripheral blood of MS patients prior to treatment could serve a role as biomarker for the differential clinical response to IFNß
Two class paired analysis using Significant Analysis of Microarrays (SAM) at a False Discovery Rate (FDR) of less than 5% between pre- and post-therapy data was applied to identify genes that significantly changed in expression after IFNß treatment
Summary
Multiple sclerosis (MS) is a common inflammatory disease of the central nervous system characterized by progressive neurological dysfunction. Interferon beta (IFNß) decreases clinical relapses, reduces brain disease activity, and possibly slows down progression of disability. The response to IFNß is partial, i.e. disease activity is suppressed by only about one third.[2] Clinical experience suggests that there are IFN ‘responders’ as well as ‘non responders’, clear criteria for such classification are still lacking.[3] In the absence of predictive biomarkers the question remains who will respond to therapy and who to treat when inconvenience and costs are significant. Multiple sclerosis (MS) is a heterogeneous disease. In order to understand the partial responsiveness to IFNß in Relapsing Remitting MS (RRMS) we studied the pharmacological effects of IFNß therapy
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