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P042 Targeting NF-Κb signalling in B cells: a potential new treatment modality for antibody mediated autoimmune diseases
  1. JP Van Hamburg1,
  2. P Tuijnenburg2,
  3. B Helder1,
  4. L van Keep1,
  5. K Wesenhagen1,
  6. P Kucharzewka3,
  7. MH Jansen2,
  8. A Al-Soudi1,
  9. PL Klarenbeek1,
  10. H Olsson3,
  11. N de Vries1,
  12. T Kuijpers2,
  13. SW Tas1
  1. 1Amsterdam Rheumatology and Immunology Centre, Academic Medical Centre/University of Amsterdam
  2. 2Department of Experimental Immunology, Academic Medical Centre/University of Amsterdam, Amsterdam, Netherlands
  3. 3Respiratory, Inflammation and Autoimmunity IMED Biotech Unit, AstraZeneca, Gothenburg, Sweden


Introduction The pivotal role of B cells in the pathogenesis autoimmune diseases such as ANCA-associated vasculitis (AAV) is well-established and further substantiated by beneficial therapeutic effects of rituximab (anti-CD20 B cell targeted therapy). However, this results in prolonged B cell depletion while long-lived plasma cells are not targeted. Thus there is a need for novel therapeutics targeting cells in the B-cell lineage in AAV. Novel targets might be encountered in the NF-κB signalling pathway, which acts downstream of various B cell surface receptors, including the B cell antigen receptor, CD40, BAFFR and TLRs, and is crucially involved in B cell responses.

Objectives To identify whether inhibition of NF-κB signalling by novel pharmacological inhibitors is effective in targeting B cell responses in general and more specifically blocks (auto)antibody production and plasmablast differentiation in B cells from AAV patients.

Methods PBMC and sorted B cells from AAV patients and healthy donors were cultured with T cell-dependent (anti-IgM +anti CD40+IL-21) and T cell-independent (CpG +IL-2) stimuli. NF-κB signalling was targeted in these cultures by small molecule inhibitors of NF-κB inducing kinase (NIK, non-canonical NF-κB signalling) and IKKβ (canonical NF-κB signalling). Downstream NF-κB signalling and nuclear NF-κB translocation was determined by Western blot and confocal imaging. Effects on B cell proliferation and differentiation were determined by CFSE dilution assays and flow cytometric analysis of B cell markers. (Auto)antibody production was measured by ELISA.

Results In B cells, targeting of NIK and IKKβ effectively inhibited non-canonical or canonical NF-κB signalling, respectively. In a B cell stimulation assay, NIK and IKKβ inhibition significantly reduced T cell-dependent (anti-IgM +anti CD40+IL-21) and T cell-independent (CpG +IL-2) B cell proliferation, plasmablast differentiation (CD27++/CD38+), and antibody production. The effects of NIK inhibition appeared to be B cell-specific as T cell proliferation was largely unaffected. Currently, studies are ongoing to investigate the effect of IKKβ inhibition on B cell responses and to explore the effects of targeting NF-κB signalling in AAV B cells.

Conclusions These data demonstrate that inhibition of NF-κB signalling in B cells results in the modulation of various B cell responses. Ongoing studies will indicate whether targeting of NF-κB signalling in B cells may be an effective novel treatment modality for AAV.

Disclosure of interest None declared

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