Absence of MxA induction by interferon beta in patients with MS reflects complete loss of bioactivity.
BACKGROUND
In patients with multiple sclerosis (MS), neutralizing antibodies (NAbs) appearing during treatment with interferon (IFN) beta reduce or in high concentrations abolish bioactivity and therapeutic efficacy. In vivo MxA induction by IFNbeta is used as a marker of biologic response to IFNbeta. 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 IFNbeta 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 IFNbeta-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 IFNbeta-regulated genes at a 5% level in NAb-negative patients. The corresponding number of IFNbeta-regulated genes in NAb-positive patients was zero.


CONCLUSIONS
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) beta-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 IFNbeta, with no indication of residual bioactivity.
Hesse
D
D
Danish Multiple Sclerosis Research Center, Department of Neurology 2082, Copenhagen University Hospital Rigshospitalet, Denmark. dan.hesse@rh.regionh.dk
Sellebjerg
F
F
Sorensen
P Soelberg
PS
D000328:Adult; D000906:Antibodies / Q000097:blood*; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D015331:Cohort Studies; D005260:Female; D019204:GTP-Binding Proteins / Q000032:analysis / Q000097:blood*; D020869:Gene Expression Profiling / Q000379:methods; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000276:immunology; D006801:Humans; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000188:drug therapy* / Q000276:immunology; D064547:Myxovirus Resistance Proteins; D020411:Oligonucleotide Array Sequence Analysis; D011237:Predictive Value of Tests; D015203:Reproducibility of Results; D016896:Treatment Outcome; D055815:Young Adult
D000906:Antibodies; D015415:Biomarkers; C579071:MX1 protein, human; D064547:Myxovirus Resistance Proteins; D016899:Interferon-beta; D019204:GTP-Binding Proteins