Identification of new sensitive biomarkers for the in vivo response to interferon-beta treatment in multiple sclerosis using DNA-array evaluation.
OBJECTIVE
Neutralizing antibodies (NAbs) occur in a proportion of multiple sclerosis (MS) patients treated with interferon (IFN)-beta. NAbs impair the effect of treatment. The biological effect of IFN-beta 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-beta. We used DNA array analysis to identify genes that are strongly induced in blood cells by IFN-beta, 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-beta 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-beta. 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.


CONCLUSIONS
We identify IFI27, CCL2 and CXCL10 as sensitive biomarkers for the response to IFN-beta. 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.
Sellebjerg
F
F
Department of Neurology, Danish Multiple Sclerosis Research Center, Copenhagen University Hospital Rigshospitalet, Copenhagen, Denmark. sellebjerg@dadlnet.dk
Krakauer
M
M
Hesse
D
D
Ryder
L P
LP
Alsing
I
I
Jensen
P E H
PE
Koch-Henriksen
N
N
Svejgaard
A
A
Soelberg Sørensen
P
P
D057134:Antibodies, Neutralizing / Q000097:blood; D015415:Biomarkers / Q000032:analysis*; D018932:Chemokine CCL2 / Q000096:biosynthesis / Q000235:genetics; D054357:Chemokine CXCL10 / Q000096:biosynthesis / Q000235:genetics; D004351:Drug Resistance / Q000235:genetics*; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use*; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D020133:Reverse Transcriptase Polymerase Chain Reaction
D057134:Antibodies, Neutralizing; D015415:Biomarkers; C111835:CCL2 protein, human; D018932:Chemokine CCL2; D054357:Chemokine CXCL10; C406887:IFI27 protein, human; D007155:Immunologic Factors; D008565:Membrane Proteins; D016899:Interferon-beta