Your browser version may not work well with NCBI's Web applications. More information here...
1: Nat Med. 2008 Jul;14(7):748-55. Epub 2008 Jun 8.
Related Articles, Links
Click here to read Click here to read Click here to read
The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis.

Neubert K, Meister S, Moser K, Weisel F, Maseda D, Amann K, Wiethe C, Winkler TH, Kalden JR, Manz RA, Voll RE.

Interdisciplinary Center for Clinical Research, research group N2, Nikolaus Fiebiger-Center of Molecular Medicine, University Hospital Erlangen, Glückstrasse 6, 91054 Erlangen, Germany.

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.

Publication Types:
PMID: 18542049 [PubMed - indexed for MEDLINE]