Article Text

Download PDFPDF

P042 Targeting NF-Κb signalling in B cells: a potential new treatment modality for antibody mediated autoimmune diseases
Free
  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

Abstract

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

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.