Article abstract
Nature Medicine 14, 748 - 755 (2008)
Published online: 8 June 2008 | doi:10.1038/nm1763
The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis
Kirsten Neubert1, Silke Meister1, Katrin Moser2, Florian Weisel3, Damian Maseda1, Kerstin Amann4, Carsten Wiethe5, Thomas H Winkler3, Joachim R Kalden6, Rudolf A Manz2 & Reinhard E Voll1,6
Abstract
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.
- Interdisciplinary Center for Clinical Research, research group N2, Nikolaus Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Glückstrasse 6, 91054 Erlangen, Germany.
- Department for Humoral Immunology, German Arthritis Research Center, Schumannstrasse 21/22, 10117 Berlin, Germany.
- Hematopoiesis Unit, Department Biology, University of Erlangen-Nuremberg, Glückstrasse 6, 91054 Erlangen, Germany.
- Institute for Pathology, University of Erlangen-Nuremberg, Ramistrasse 100, 91054 Erlangen, Germany.
- Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, 91054 Erlangen, Germany.
- Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, 91054 Erlangen, Germany.
Correspondence to: Reinhard E Voll1,6 e-mail: rvoll@molmed.uni-erlangen.de
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