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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Arthritis+Rheum
2012 ; 64
(2
): 493-503
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Beneficial effect of novel proteasome inhibitors in murine lupus via dual
inhibition of type I interferon and autoantibody-secreting cells
#MMPMID21905015
Ichikawa HT
; Conley T
; Muchamuel T
; Jiang J
; Lee S
; Owen T
; Barnard J
; Nevarez S
; Goldman BI
; Kirk CJ
; Looney RJ
; Anolik JH
Arthritis Rheum
2012[Feb]; 64
(2
): 493-503
PMID21905015
show ga
OBJECTIVE: To investigate the hypothesis that proteasome inhibition may have
potential in the treatment of SLE, by targeting plasmacytoid dendritic cells
(PDCs) and plasma cells, both of which are critical in disease pathogenesis.
METHODS: Lupus-prone mice were treated with the nonselective proteasome
inhibitors carfilzomib and bortezomib, the immunoproteasome inhibitor ONX 0914,
or vehicle control. Tissue was harvested and analyzed by flow cytometry using
standard markers. Nephritis was monitored by evaluation for proteinuria and by
histologic analysis of kidneys. Serum anti-double-stranded DNA (anti-dsDNA)
levels were measured by enzyme-linked immunosorbent assay (ELISA), and total IgG
and dsDNA antibody-secreting cells (ASCs) by enzyme-linked immunospot assay.
Human peripheral blood mononuclear cells or mouse bone marrow cells were
incubated with Toll-like receptor (TLR) agonists and proteasome inhibitors, and
interferon-? (IFN?) levels were measured by ELISA and flow cytometry. RESULTS:
Early treatment of lupus-prone mice with the dual-targeting proteasome inhibitors
carfilzomib or bortezomib or the immunoproteasome-specific inhibitor ONX 0914
prevented disease progression, and treatment of mice with established disease
dramatically abrogated nephritis. Treatment had profound effects on plasma cells,
with greater reductions in autoreactive than in total IgG ASCs, an effect that
became more pronounced with prolonged treatment and was reflected in decreasing
serum autoantibody levels. Notably, proteasome inhibition efficiently suppressed
production of IFN? by TLR-activated PDCs in vitro and in vivo, an effect mediated
by inhibition of both PDC survival and PDC function. CONCLUSION: Inhibition of
the immunoproteasome is equally efficacious as dual targeting agents in
preventing lupus disease progression by targeting 2 critical pathways in disease
pathogenesis, type I IFN activation and autoantibody production by plasma cells.