IFN-b-1a Therapy Induces the Expansion of TGF-β1-Producing B-Cells and FOXP3+ T-Regulatory Cells in Patients with Relapsing-Remitting Multiple Sclerosis (RRMS) (P5.286)

Background: The role TGF-β+ B-regulatory cells has not been examined in RRMS.Objectives: To investigate the in-vivo effect of IFNβ-1a (Avonex) therapy on the B-cell regulation of the inflammatory response in RRMS.Methods: Blood samples were collected at baseline, and months 3, 6 and 12 after IFNβ-1a in-vivo therapy from 16 RRMS patients. Intracellular cytokine staining in CD19-gated B-cells and CD4+ T-cells, gene expression studies in separated B-cells and CD4+ T-cells and cytokine serum measurements were correlated with baseline and month 12 brain MRI lesion volumes.Results: IFNβ-1a therapy significantly increased the TGF-β1 gene expression in CD19+ B-cells and the percentage of TGF-β1-producing B-cells at month 12 post-therapy. The treatment increased FOXP3 gene expression in CD4+ T-cells at 12 months, and decreased IL-21 gene expression at months 6 and 12, and the percentage of IL-21-secreting CD4+ T-cells at month 12. IFNβ-1a therapy significantly increased the serum TGF-β1 level at month 12, and decreased IL-17A, IL-21, IL-23 and IL-15 at months 6 and 12. We found a positive correlation between B-cell TGF-β1 and CD4+ cells’ FOXP3 gene expression, and negative correlation between the percentage of TGF-β1+ B-cells and IL-21+CD4+ cells over duration of the study. The importance of IL-21+CD4+ cells in the development of the CNS inflammatory lesions was demonstrated by a positive correlation between baseline percentage of IL-21+CD4+ cells and T2 brain MRI lesion volume and a negative correlation with the brain parenchymal fraction (BPF) volume. In addition, baseline percentage of IL-21+CD4+ cells positively correlated with change in T1 lesion volume from baseline to month 12 and with the total T2 lesion volume at month 12 post therapy, and negatively correlated with BPF volume at month 12.Conclusions: The expansion of TGF-b1+ B-cells, which may induce FOXP3+CD4+ Treg and inhibit IL-21+CD4+ T-cell responses, may represent IFNb-1a’s novel mechanism of action. Disclosure: Dr. Markovic Plese has received personal compensation for activities with Genzyme Inc. Dr. Tao has nothing to disclose. Dr. Zhang has received personal compensation for activities with EMD Serono. Dr. Kim has nothing to disclose. Dr. Bruce has nothing to disclose. Dr. Yang has nothing to disclose. Dr. Townsend has nothing to disclose. Dr. Pruteanu-Malinici has nothing to disclose. Dr. Buch has nothing to disclose. Dr. Dunn has nothing to disclose. Dr. Kurtoglu has nothing to disclose. Dr. Kong has nothing to disclose. Dr. Craddock has nothing to disclose. Dr. Chopra has nothing to disclose. Dr. Zhu has nothing to disclose. Dr. Jewells has nothing to disclose.