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NEUROLOGY 2009;73:372-377
© 2009 American Academy of Neurology

Absence of MxA induction by interferon β in patients with MS reflects complete loss of bioactivity

D. Hesse, MD, F. Sellebjerg, MD, DMSc and P. Soelberg Sorensen, MD, DMSc

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

Address correspondence and reprint requests to Dr. Dan Hesse, Danish Multiple Sclerosis Research Center, Department of Neurology 2082, Copenhagen University Hospital Rigshospitalet, Denmark dan.hesse{at}rh.regionh.dk

Background: In patients with multiple sclerosis (MS), neutralizing antibodies (NAbs) appearing during treatment with interferon (IFN) β reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNβ is used as a marker of biologic response to IFNβ. It has been argued that despite absence of MxA induction measured by PCR, some bioactivity might be preserved. In a cohort study, we measured gene expression by gene chip analysis in NAb-negative and NAb-positive patients to test that hypothesis.

Methods: The effect of IFNβ was studied by comparing samples collected before and 9–12 hours after an injection. The cohort consisted of 12 NAb-positive patients without MxA response and 12 NAb-negative patients with preserved response. MxA in vivo response was determined in whole blood using real-time PCR. Screening for IFNβ-regulated genes in mononuclear cells was done using gene chips. False discovery rate (FDR) analysis was used as statistical tool.

Results: Of 8,793 genes, 5,593 were detectable in at least one patient in both groups. Of these, calculation of FDR revealed 1,077 IFNβ-regulated genes at a 5% level in NAb-negative patients. The corresponding number of IFNβ-regulated genes in NAb-positive patients was zero.

Conclusion: In neutralizing antibody (NAb)–positive patients without an MxA response, we were not able to detect differential expression of any of the 1077 interferon (IFN) β-regulated genes identified in NAb-negative patients. Lack of MxA in vivo response in patients with multiple sclerosis with NAbs is a reliable marker of a completely blocked biologic response to IFNβ, with no indication of residual bioactivity.

Abbreviations: FDR = false discovery rate; IL10 = interleukin-10; IFI27 = interferon, alpha-inducible protein 27; IFN = interferon; MS = multiple sclerosis; NAb = neutralizing antibody; NR = normalization ratio; TRAIL = tumor necrosis factor–related apoptosis-inducing ligand; TRU = 10-fold reduction unit.

This work was performed as a part of the Neutralizing Antibodies in Multiple Sclerosis (NABINMS) Project supported by the European Union Sixth Framework Programme: Life sciences, Genomics and Biotechnology for health.

Disclosure: Author disclosures are provided at the end of the article.

Received February 24, 2009. Accepted in final form April 20, 2009.






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