Changes in Immunological Biomarkers in Patients with Relapsing-Remitting Multiple Sclerosis Treated with Interferon Beta-1a (P4.132)

Field: Medicine (Health Sciences)

OBJECTIVE: Compare percentages of CD4+ T-cells producing Th17/Th2 and Th1/Th2 cytokines and transcription factor gene expression ratios in relapsing-remitting multiple sclerosis (RRMS) patients versus healthy controls (HCs); measure changes in these biomarkers following 6 months’ treatment with interferon (IFN) beta-1a subcutaneously (SC).
BACKGROUND: Shifting from a Th17- or Th1- to a Th2-cytokine profile may ameliorate RRMS disease activity.
DESIGN/METHODS: Blood samples were collected from 15 HCs at baseline, and from 23 RRMS patients at baseline and after 6 months’ treatment with IFN beta-1a SC three times weekly (NCT01085318). The percentage of CD4+ T-cells expressing a cytokine protein of interest was determined by flow cytometry (FACS); relative gene expression, normalized against 18S mRNA, was measured by quantitative real-time polymerase chain reaction (qRT-PCR). Differences in immunological biomarker ratios between RRMS patients and HCs at baseline, and changes over 6 months in RRMS patients after IFN beta-1a treatment, were analyzed post-hoc using Student’s t-tests.
RESULTS: At baseline, interleukin (IL)-21/IL-4 and IL-22/IL-4 expression ratios in CD4+ T-cells were significantly higher in RRMS patients than HCs (fold difference of 1.6-4.6; p<0.05). IL-17F/IL-4 gene expression ratio was also higher (5-fold) in RRMS patients than HCs (p=0.005). In RRMS patients, after 6 months’ IFN beta-1a SC treatment, protein and gene expression ratios for IL-17F/IL-4, protein expression for IL‐22/IL-4 and gene expression for IL-21/IL-4 decreased significantly (p<0.005) to HC baseline values. Although T-bet/GATA-3 gene expression ratios did not differ between RRMS patients and HCs, this ratio in patients decreased 40-fold after IFN beta-1a SC (p=0.0002).
CONCLUSIONS: Reduction of ratios of pro-inflammatory to anti-inflammatory cytokine expression, and of Th1 to Th2 transcription factor gene expression, in CD4+ T-cells in RRMS patients following 6 months’ IFN beta-1a SC treatment suggests they could be used as potential biomarkers of the therapeutic efficacy of IFN beta-1a in RRMS patients.
Study Supported by: EMD Serono, Inc., Rockland, MA,* and Pfizer Inc, New York. (*A subsidiary of Merck KGaA, Darmstadt, Germany) Disclosure: Dr. Zhang has received personal compensation for activities with EMD Serono. Dr. Tao has received personal compensation for activities with EMD Serono. Dr. Weinstock-Guttman has received personal compensation for activities with Biogen Idec, Teva Neuroscience, EMD Serono, Pfizer, Novartis, Genzyme, Sanofi-Aventis Pharmaceuticals, Inc., Mylan, and Acorda Therapeutics. Dr. Weinstock-Guttman has received research support from Biogen Idec, Teva Neuroscience, EMD Serono, Pfizer Inc, Novartis, Acorda, ITN, Questcor, Shire, Genzyme, Sanofi-Aventis Pharmaceuticals, Inc., National Multiple Sclerosis Society, the National Institutes of Health and Aspreva-Roche. Dr. Zivadinov has received personal compensation for activities with Teva, Biogen Idec, EMD Serono, Novartis, Claret and Sanofi-Genzyme. Dr. Zivadinov has received research support from Biogen Idec, Teva Pharmaceuticals, Sanofi-Genzyme, Novartis and EMD Serono. Dr. Hayward has received personal compensation for activities with EMD Serono as an employee. Dr. Dangond has received personal compensation for activities with EMD Serono, Inc. Dr. Markovic has received personal compensation for activities with EMD Serono. Dr. Markovic has received research support from EMD Serono, Biogen Idec., and Genzyme Corp.