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

Authors: Sellebjerg, F.¹; Krakauer, M.¹; Hesse, D.¹; Ryder, L. P.²; Alsing, I.²; Jensen, P. E. H.¹; Koch-Henriksen, N.³; Svejgaard, A.²; Soelberg Sørensen, P.¹

Source: European Journal of Neurology, Volume 16, Number 12, December 2009 , pp. 1291-1298(8)

Publisher: Wiley-Blackwell

Abstract:

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.

Keywords: biomarkers; gene expression; interferon-β; multiple sclerosis; neutralizing antibodies

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1468-1331.2009.02716.x

Affiliations: 1: Department of Neurology, Danish Multiple Sclerosis Research Center, Copenhagen University Hospital Rigshospitalet, Copenhagen Denmark 2: Department of Clinical Immunology, Tissue Typing Laboratory, Copenhagen University Hospital Rigshospitalet, Copenhagen Denmark 3: Department of Neurology, Aalborg Hospital, Aalborg, Denmark

Publication date: 2009-12-01

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• In this Subject: Neurology & Psychiatry ,  Public Health
• By this author: Sellebjerg, F. ;  Krakauer, M. ;  Hesse, D. ;  Ryder, L. P. ;  Alsing, I. ;  Jensen, P. E. H. ;  Koch-Henriksen, N. ;  Svejgaard, A. ;  Soelberg Sørensen, P.

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