Contributions
Abstract: 100
Type: Young Scientific Investigators' Session
Abstract Category: Pathology and pathogenesis of MS - Biomarkers
Introduction: In multiple sclerosis (MS), B cell depleting anti-CD20 antibodies efficiently reduce relapses and central nervous system lesions by abrogating B cell antigen presenting function and secretion of pro-inflammatory cytokines, e.g. interleukin (IL)-6. However, not all B cells are harmful and instead regulate other immune cells via anti-inflammatory cytokines, such as IL-10. Here, we studied how anti-CD20-mediated absence of B cells affects frequency, cytokine production and activation of myeloid antigen-presenting cells (APC), which are tightly regulated by B cells. Further, we investigated whether the B cell phenotype prior to anti-CD20 treatment predicts the extent of myeloid APC activation upon therapeutic B cell removal.
Methods: To elucidate the influence of B cells on myeloid APC, murine macrophages, B and T cells were co-cultured in various settings. To study the effects of anti-CD20 treatment, peripheral blood mononuclear cells of MS patients were collected before and several months after treatment initiation. The B cell phenotype and cytokine signature was determined by flow cytometry, activation and cytokine signature of myeloid cells by flow cytometry and ELISPOT.
Results: In our co-culture setting, we identified a triangle of B cells, myeloid cells and T cells, in which B cell-derived IL-6 activated myeloid APC resulting in an enhanced T cell activation. Conversely, IL-10 produced by B cells regulated the APC-T cell axis in an anti-inflammatory manner. Anti-CD20 mediated absence of B cells in MS patients reflected these interactions, as treatment resulted in both, individuals with increased or reduced monocyte activity. In ongoing experiments, we investigate whether the changes in the activation of myeloid APC upon anti-CD20 treatment correlate with the preexisting B cell phenotype.
Conclusion: Our mechanistic studies revealed that the cytokine milieu generated by B cells is capable of differentially shaping the activity and antigen-presenting capacity of myeloid cells. While in most patients with MS, anti-CD20 treatment resulted in a desirable immunological outcome, others displayed an accentuated activation of immune cells. We hypothesize that the individual B cell phenotype before anti-CD20 treatment predicts the respective immunological changes thereafter. Hereby, we aim to generate an immunological, and in perspective clinical biomarker which identifies individuals who should not primarily receive a B cell-depleting therapy.
Disclosure: 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. S. Kinzel is supported by the research program of the university medical center Göttingen.
Abstract: 100
Type: Young Scientific Investigators' Session
Abstract Category: Pathology and pathogenesis of MS - Biomarkers
Introduction: In multiple sclerosis (MS), B cell depleting anti-CD20 antibodies efficiently reduce relapses and central nervous system lesions by abrogating B cell antigen presenting function and secretion of pro-inflammatory cytokines, e.g. interleukin (IL)-6. However, not all B cells are harmful and instead regulate other immune cells via anti-inflammatory cytokines, such as IL-10. Here, we studied how anti-CD20-mediated absence of B cells affects frequency, cytokine production and activation of myeloid antigen-presenting cells (APC), which are tightly regulated by B cells. Further, we investigated whether the B cell phenotype prior to anti-CD20 treatment predicts the extent of myeloid APC activation upon therapeutic B cell removal.
Methods: To elucidate the influence of B cells on myeloid APC, murine macrophages, B and T cells were co-cultured in various settings. To study the effects of anti-CD20 treatment, peripheral blood mononuclear cells of MS patients were collected before and several months after treatment initiation. The B cell phenotype and cytokine signature was determined by flow cytometry, activation and cytokine signature of myeloid cells by flow cytometry and ELISPOT.
Results: In our co-culture setting, we identified a triangle of B cells, myeloid cells and T cells, in which B cell-derived IL-6 activated myeloid APC resulting in an enhanced T cell activation. Conversely, IL-10 produced by B cells regulated the APC-T cell axis in an anti-inflammatory manner. Anti-CD20 mediated absence of B cells in MS patients reflected these interactions, as treatment resulted in both, individuals with increased or reduced monocyte activity. In ongoing experiments, we investigate whether the changes in the activation of myeloid APC upon anti-CD20 treatment correlate with the preexisting B cell phenotype.
Conclusion: Our mechanistic studies revealed that the cytokine milieu generated by B cells is capable of differentially shaping the activity and antigen-presenting capacity of myeloid cells. While in most patients with MS, anti-CD20 treatment resulted in a desirable immunological outcome, others displayed an accentuated activation of immune cells. We hypothesize that the individual B cell phenotype before anti-CD20 treatment predicts the respective immunological changes thereafter. Hereby, we aim to generate an immunological, and in perspective clinical biomarker which identifies individuals who should not primarily receive a B cell-depleting therapy.
Disclosure: 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. S. Kinzel is supported by the research program of the university medical center Göttingen.