Format

Send to

Choose Destination
J Am Soc Nephrol. 2011 Feb;22(2):336-48. doi: 10.1681/ASN.2010010034. Epub 2011 Jan 13.

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

Author information

1
Experimental and Clinical Research Center at the Charité and Max-Delbrück-Center for Molecular Medicine, Lindenberger Weg 80, 13125 Berlin, Germany.

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.

PMID:
21233415
PMCID:
PMC3029906
DOI:
10.1681/ASN.2010010034
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center