Identification of new sensitive biomarkers for the in vivo response to interferon-β treatment in multiple sclerosis using DNA-array evaluation

• Published in: European journal of neurology Vol. 16; no. 12; pp. 1291 - 1298
• Main Authors: Sellebjerg, F., Krakauer, M., Hesse, D., Ryder, L. P., Alsing, I., Jensen, P. E. H., Koch-Henriksen, N., Svejgaard, A., Soelberg Sørensen, P.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2009
• Subjects: Antibodies, Neutralizing - blood; biomarkers; Biomarkers - analysis; Chemokine CCL2 - biosynthesis; Chemokine CCL2 - genetics; Chemokine CXCL10 - biosynthesis; Chemokine CXCL10 - genetics; Drug Resistance - genetics; Gene Expression; Gene Expression Profiling; Humans; Immunologic Factors - therapeutic use; Interferon-beta - therapeutic use; interferon-β; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - drug therapy; Multiple Sclerosis - genetics; neutralizing antibodies; Oligonucleotide Array Sequence Analysis; Reverse Transcriptase Polymerase Chain Reaction
• ISSN: 1351-5101; 1468-1331
• DOI: 10.1111/j.1468-1331.2009.02716.x

Objective:  Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)‐β. NAbs impair the effect of treatment. The biological effect of IFN‐β can be measured as the induction of the myxovirus resistance protein A (MxA) molecule. However, other markers could be more sensitive for evaluating the response to IFN‐β. We used DNA array analysis to identify genes that are strongly induced in blood cells by IFN‐β, and measured their expression in MS patients with different NAb levels. Methods:  Gene expression was studied on DNA arrays in untreated patients, in NAb negative patients, and in MS patients with varying NAb levels 9–12 h and 36–48 h after IFN‐β administration. The expression of selected genes was measured by real‐time PCR. NAb levels were assessed by a cytopathic effect assay. Results:  Several hundred genes were induced 9–12 h after an injection of IFN‐β. The molecules CXCL10, CCL2 and IFI27 were among the most strongly induced. Gene induction was generally much less pronounced after 36–48 h, but IFI27 remained strongly induced. The strong induction of these molecules and MxA was confirmed by real‐time PCR. Induction of MxA, CCL2, CXCL10 and IFI27 was reduced in patients with low NAb levels and lost in patients with intermediate/high NAb levels. Conclusion:  We identify IFI27, CCL2 and CXCL10 as sensitive biomarkers for the response to IFN‐β. The expression of these markers adequately reflects bioactivity of IFN‐ß as documented by the decreased induction in low NAb‐positive patients and the lost induction in patients with moderate/high NAb levels.