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

  1. F. Sellebjerg1,
  2. M. Krakauer1,
  3. D. Hesse1,
  4. L. P. Ryder2,
  5. I. Alsing2,
  6. P. E. H. Jensen1,
  7. N. Koch-Henriksen3,
  8. A. Svejgaard2,
  9. P. Soelberg Sørensen1

Article first published online: 22 JUN 2009

DOI: 10.1111/j.1468-1331.2009.02716.x

Issue

European Journal of Neurology

European Journal of Neurology

Volume 16, Issue 12, pages 1291–1298, December 2009

Additional Information

How to Cite

Sellebjerg, F., Krakauer, M., Hesse, D., Ryder, L. P., Alsing, I., Jensen, P. E. H., Koch-Henriksen, N., Svejgaard, A. and Soelberg Sørensen, P. (2009), Identification of new sensitive biomarkers for the in vivo response to interferon-β treatment in multiple sclerosis using DNA-array evaluation. European Journal of Neurology, 16: 1291–1298. doi: 10.1111/j.1468-1331.2009.02716.x

Author Information

  1. 1

    Department of Neurology, Danish Multiple Sclerosis Research Center, Copenhagen University Hospital Rigshospitalet, Copenhagen Denmark

  2. 2

    Department of Clinical Immunology, Tissue Typing Laboratory, Copenhagen University Hospital Rigshospitalet, Copenhagen Denmark

  3. 3

    Department of Neurology, Aalborg Hospital, Aalborg, Denmark

*Dr Finn Sellebjerg, Department of Neurology, Danish Multiple Sclerosis Research Center, Copenhagen University Hospital Rigshospitalet, DK2100 Copenhagen, Denmark (tel.: +45 3545 6707; fax: +45 3545 2626; e-mail: sellebjerg@dadlnet.dk).

Publication History

  1. Issue published online: 17 NOV 2009
  2. Article first published online: 22 JUN 2009
  3. Received 4 March 2009 Accepted 7 May 2009

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Keywords:

  • biomarkers;
  • gene expression;
  • interferon-β;
  • multiple sclerosis;
  • neutralizing antibodies

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.

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