Contributions
Abstract: EP1609
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Introduction: Dimethyl fumarate (DMF) is commonly used for treatment of multiple sclerosis (MS). Its effects on the peripheral immune system and especially on B lymphocytes are not entirely understood. B cells are increasingly recognized to play a crucial role in the pathogenesis of MS though, acting both as antigen-presenting cells (APC) for the activation of T cells as well as by provision of immune cell-polarizing cytokines. Hence, we investigated whether and how DMF modulates B cell phenotype and function in treatment of MS.
Methods: We analyzed peripheral blood mononuclear cells from 30 DMF- and 31 non-DMF treated control patients by flow cytometry; six individual patients were analyzed before and 6 months after DMF treatment initiation. Frequency of T cells, monocytes and B cells was assessed. B cell subsets were evaluated for surface expression of CD19, CD20, CD24, CD27 and CD38, identifying various maturation stages of B cells. We determined expression of activation markers (CD25, CD69, CD95), molecules involved in antigen presentation (CD40, CD80, CD86, MHC-II) and the production of cytokines (IL-6, IL-10, TNF) by monocytes and B cells.
Results: As reported previously, the frequency of CD8+ T cells was decreased in DMF-treated patients, with a compensatory increase in CD4+ T cells. The frequency of monocytes was elevated with a yet diminished production of pro-inflammatory cytokines. While the frequency of B cells was unchanged, we observed a lower frequency of mature, activated and memory B cells as well as plasmablasts. Furthermore, we observed a reduced production of pro-inflammatory TNF and IL-6 as well as a lower expression of activation markers. Conversely, we determined an increased frequency of naïve and early transitional B cells. DMF reduced the expression of CD40, CD80 and CD86, whereas MHC-II expression was significantly upregulated upon initiation of DMF treatment.
Conclusions: Our study reveals that the compartment of B lymphocytes is substantially affected by DMF treatment, with a pronounced impairment of activated and mature B cell phenotypes. These findings are in line with the hypothesis that DMF primarily targets immune cells with a high metabolic turnover. While impairment of B cell differentiation by DMF likely translates into clinical benefit, current investigations aim to clarify how the observed increase in MHC-II expression by B cells affects their APC function.
Disclosure: J. Traub recieves support from the "VorSPrUNG Promotionskolleg" of the department of neurology in Göttingen. H. Pellkofer: nothing to disclose. J. Ochs: nothing to disclose. S. Kinzel was supported by the research program of the university medical center Göttingen. M. S. Weber receives research support from the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. M.S.W. is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme.
Abstract: EP1609
Type: Poster Sessions
Abstract Category: Therapy - Immunomodulation/Immunosuppression
Introduction: Dimethyl fumarate (DMF) is commonly used for treatment of multiple sclerosis (MS). Its effects on the peripheral immune system and especially on B lymphocytes are not entirely understood. B cells are increasingly recognized to play a crucial role in the pathogenesis of MS though, acting both as antigen-presenting cells (APC) for the activation of T cells as well as by provision of immune cell-polarizing cytokines. Hence, we investigated whether and how DMF modulates B cell phenotype and function in treatment of MS.
Methods: We analyzed peripheral blood mononuclear cells from 30 DMF- and 31 non-DMF treated control patients by flow cytometry; six individual patients were analyzed before and 6 months after DMF treatment initiation. Frequency of T cells, monocytes and B cells was assessed. B cell subsets were evaluated for surface expression of CD19, CD20, CD24, CD27 and CD38, identifying various maturation stages of B cells. We determined expression of activation markers (CD25, CD69, CD95), molecules involved in antigen presentation (CD40, CD80, CD86, MHC-II) and the production of cytokines (IL-6, IL-10, TNF) by monocytes and B cells.
Results: As reported previously, the frequency of CD8+ T cells was decreased in DMF-treated patients, with a compensatory increase in CD4+ T cells. The frequency of monocytes was elevated with a yet diminished production of pro-inflammatory cytokines. While the frequency of B cells was unchanged, we observed a lower frequency of mature, activated and memory B cells as well as plasmablasts. Furthermore, we observed a reduced production of pro-inflammatory TNF and IL-6 as well as a lower expression of activation markers. Conversely, we determined an increased frequency of naïve and early transitional B cells. DMF reduced the expression of CD40, CD80 and CD86, whereas MHC-II expression was significantly upregulated upon initiation of DMF treatment.
Conclusions: Our study reveals that the compartment of B lymphocytes is substantially affected by DMF treatment, with a pronounced impairment of activated and mature B cell phenotypes. These findings are in line with the hypothesis that DMF primarily targets immune cells with a high metabolic turnover. While impairment of B cell differentiation by DMF likely translates into clinical benefit, current investigations aim to clarify how the observed increase in MHC-II expression by B cells affects their APC function.
Disclosure: J. Traub recieves support from the "VorSPrUNG Promotionskolleg" of the department of neurology in Göttingen. H. Pellkofer: nothing to disclose. J. Ochs: nothing to disclose. S. Kinzel was supported by the research program of the university medical center Göttingen. M. S. Weber receives research support from the Deutsche Forschungsgemeinschaft (DFG; WE 3547/5-1), from Novartis, TEVA, Biogen-Idec, Roche, Merck and the ProFutura Programm of the Universitätsmedizin Göttingen. M.S.W. is serving as an editor for PLoS One. He received travel funding and/or speaker honoraria from Biogen-Idec, Merck Serono, Novartis, Roche, TEVA, Bayer and Genzyme.