Dynamics of interferon-beta modulated mRNA biomarkers in multiple sclerosis patients with anti-interferon-beta neutralizing antibodies.
The objective of this study was to evaluate multiple interferon (IFN) specific mRNA biomarkers in multiple sclerosis (MS) patients with anti-IFN-beta neutralizing antibodies (NAB) using a pharmacodynamic study design. Thirty patients were enrolled. Blood samples were drawn at pre-treatment, 4-, 8-h time points following the intramuscular dose of IFN-beta-1a. Total RNA was obtained from peripheral blood cells, processed to cDNA and analyzed using quantitative real-time polymerase chain reaction. Pre-treatment serum samples were analyzed for anti-IFN-beta binding and neutralizing antibodies: 22 patients were NAB negative; equal numbers of the eight remaining patients were either NAB positive or had borderline NAB status. The results showed that early assessment (at 4 h after IFN-beta injection) of mRNAs for Stat-1, MxA, MxB and TRAIL was more sensitive than the later measurements. Furthermore, the NAB positive patients had strongly attenuated gene expression responses on all the mRNAs. Patients with borderline NAB had average responses that appear to be lower than NAB negative patients on several genes, notably Stat-1, TRAIL and beta2 microglobulin.
Santos
Roseane
R
Department of Pharmaceutical Sciences, State University of New York at Buffalo, and Jacobs Neurological Institute, Buffalo General Hospital, NY 14260-1200, United States.
Weinstock-Guttman
Bianca
B
Tamaño-Blanco
Miriam
M
Badgett
Darlene
D
Zivadinov
Robert
R
Justinger
Theresa
T
Munschauer
Frederick
F
Ramanathan
Murali
M
D000328:Adult; D000906:Antibodies / Q000097:blood*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics; D015415:Biomarkers; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D016899:Interferon-beta / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger / Q000032:analysis*; D050794:STAT1 Transcription Factor / Q000235:genetics; D053221:TNF-Related Apoptosis-Inducing Ligand; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D001613:beta 2-Microglobulin / Q000235:genetics
D000906:Antibodies; D051017:Apoptosis Regulatory Proteins; D015415:Biomarkers; C579071:MX1 protein, human; C579068:MX2 protein, human; D008562:Membrane Glycoproteins; D064547:Myxovirus Resistance Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D014409:Tumor Necrosis Factor-alpha; D001613:beta 2-Microglobulin; D016899:Interferon-beta; D019204:GTP-Binding Proteins