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Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis

Item Type:Article
Title:Myeloperoxidase-specific plasma cell depletion by bortezomib protects from anti-neutrophil cytoplasmic autoantibodies-induced glomerulonephritis
Creators Name:Bontscho, J. and Schreiber, A. and Manz, R.A. and Schneider, W. and Luft, F.C. and Kettritz, R.
Abstract:Anti-neutrophil cytoplasmic autoantibodies (ANCA) cause vasculitis and necrotizing crescentic glomerulonephritis (NCGN). Steroids and cytotoxic drugs reduce mortality but can cause significant adverse events. The proteasome inhibitor bortezomib (BTZ) prevents glomerulonephritis in mouse models of lupus but its efficacy in ANCA-associated glomerulonephritis is unknown. We induced anti-MPO IgG-mediated NCGN by transplanting wild-type bone marrow (BM) into irradiated MPO-deficient mice immunized with MPO. Four weeks after BM transplantation, we treated mice with steroid/cyclophosphamide (S/CYC) or BTZ. Compared with untreated control mice, both S/CYC and BTZ significantly reduced urine abnormalities, NCGN, and infiltration of neutrophils and macrophages. Response to BTZ depended on timing of administration: BTZ abrogated NCGN if begun 3 weeks, but not 5 weeks, after BM transplantation. BTZ treatment significantly reduced total and MPO-specific plasma cells in both the spleen and bone marrow, resulting in significantly reduced anti-MPO titers. Furthermore, BTZ affected neither B cells nor total CD4 and CD8 T cells, including their naive and effector subsets. In contrast, S/CYC reduced the total number of cells in the spleen, including total and MPO-specific plasma cells and B cells. In contrast to BTZ, S/CYC did not affect total and MPO-specific plasma cells in the bone marrow. Three of 23 BTZ-treated mice died within 36 hours after BTZ administration. In summary, BTZ depletes MPO-specific plasma cells, reduces anti-MPO titers, and prevents NCGN in mice.
Keywords:Antineutrophil Cytoplasmic Antibodies, Autoantibodies, Bone Marrow Cells, Boronic Acids, Enzyme-Linked Immunospot Assay, Glomerulonephritis, Inbred C57BL Mice, Macrophages, Neutrophil Infiltration, Peroxidase, Plasma Cells, Protease Inhibitors, Pyrazines, Spleen, Animals, Mice
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:336-348
Date:February 2011
Official Publication:https://doi.org/10.1681/ASN.2010010034
PubMed:View item in PubMed

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