title: Bortezomib Plus Continuous B Cell Depletion Results in Sustained Plasma Cell Depletion and Amelioration of Lupus Nephritis in NZB/W F1 Mice.
abstract: METHODS
  NZB/W F1 mice were treated with: 1) anti-CD20, 2) anti-CD20 plus bortezomib, 3) anti-CD20 plus anti-LFA-1/anti-VLA-4 blocking antibodies, 4) anti-CD20 plus bortezomib and anti-LFA-1/anti-VLA4 blocking antibodies. Short- and long-lived plasma cells including autoreactive cells in the bone marrow and spleen were enumerated by flow cytometry and ELISPOT seven days after treatment. Based on these data in another experiment, mice received one cycle of anti-CD20 plus bortezomib followed by four cycles of anti-CD20 therapy every 10 days and were monitored for its effect on plasma cells and disease.
  
  
  RESULTS
  Short-lived plasma cells in bone marrow and spleen were efficiently depleted by all regimens targeting plasma cells. Conversely, LLPCs and anti-dsDNA-secreting plasma cells in bone marrow and spleen showed resistance to depletion and were strongly reduced by bortezomib plus anti-CD20. The effective depletion of plasma cells by bortezomib complemented by the continuous depletion of their precursor B cells using anti-CD20 promoted the persistent reduction of IgG anti-dsDNA antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice.
  
  
  CONCLUSIONS
  These findings suggest that the effective depletion of LLPCs using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, thus, might represent a promising treatment strategy for SLE and other (auto)antibody-mediated diseases.
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Laleh
authors.initials: L
authors.lastname: Khodadadi
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Alexander
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany.
authors.forename: Özen
authors.initials: Ö
authors.lastname: Sercan-Alp
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Klotsche
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Radbruch
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Falk
authors.initials: F
authors.lastname: Hiepe
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Bimba F
authors.initials: BF
authors.lastname: Hoyer
authors.affiliation: German Rheumatism Research Center Berlin (DRFZ) - a Leibniz Institute, Berlin, Germany; Department of Rheumatology and Clinical Immunology, Charité University Hospital Berlin, Berlin, Germany.
authors.forename: Adriano
authors.initials: A
authors.lastname: Taddeo
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000378:metabolism; D000970:Antineoplastic Agents / Q000627:therapeutic use; D001323:Autoantibodies / Q000276:immunology; D001402:B-Lymphocytes / Q000166:cytology*; D001853:Bone Marrow / Q000473:pathology; D000069286:Bortezomib / Q000627:therapeutic use*; D002469:Cell Separation; D004195:Disease Models, Animal; D005260:Female; D005434:Flow Cytometry; D039041:Integrin alpha4beta1 / Q000378:metabolism; D008181:Lupus Nephritis / Q000097:blood* / Q000188:drug therapy* / Q000276:immunology; D016169:Lymphocyte Function-Associated Antigen-1 / Q000378:metabolism; D051379:Mice; D008814:Mice, Inbred NZB; D010950:Plasma Cells / Q000166:cytology; D012038:Regeneration; D013154:Spleen / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D018951:Antigens, CD20; D000970:Antineoplastic Agents; D001323:Autoantibodies; D039041:Integrin alpha4beta1; D016169:Lymphocyte Function-Associated Antigen-1; D000069286:Bortezomib