The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.
Autoantibody-mediated diseases like myasthenia gravis, autoimmune hemolytic anemia and systemic lupus erythematosus represent a therapeutic challenge. In particular, long-lived plasma cells producing autoantibodies resist current therapeutic and experimental approaches. Recently, we showed that the sensitivity of myeloma cells toward proteasome inhibitors directly correlates with their immunoglobulin synthesis rates. Therefore, we hypothesized that normal plasma cells are also hypersensitive to proteasome inhibition owing to their extremely high amount of protein biosynthesis. Here we show that the proteasome inhibitor bortezomib, which is approved for the treatment of multiple myeloma, eliminates both short- and long-lived plasma cells by activation of the terminal unfolded protein response. Treatment with bortezomib depleted plasma cells producing antibodies to double-stranded DNA, eliminated autoantibody production, ameliorated glomerulonephritis and prolonged survival of two mouse strains with lupus-like disease, NZB/W F1 and MRL/lpr mice. Hence, the elimination of autoreactive plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases.
Neubert
Kirsten
K
Interdisciplinary Center for Clinical Research, research group N2, Nikolaus Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Glückstrasse 6, 91054 Erlangen, Germany.
Meister
Silke
S
Moser
Katrin
K
Weisel
Florian
F
Maseda
Damian
D
Amann
Kerstin
K
Wiethe
Carsten
C
Winkler
Thomas H
TH
Kalden
Joachim R
JR
Manz
Rudolf A
RA
Voll
Reinhard E
RE
D000818:Animals; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D019463:Mice, Inbred MRL lpr; D008814:Mice, Inbred NZB; D018448:Models, Immunological; D009393:Nephritis / Q000276:immunology / Q000517:prevention & control*; D010047:Ovalbumin; D010950:Plasma Cells / Q000187:drug effects*; D011480:Protease Inhibitors / Q000494:pharmacology*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D013997:Time Factors
D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; D010047:Ovalbumin