The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis

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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.

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Figure 1: Elimination of plasma cells from spleens and bone marrows by bortezomib treatment in NZB/W F1 mice.
Figure 2: Cellular effects after one-week treatment with bortezomib, cylophosphamide or dexamethasone in NZB/W F1 mice.
Figure 3: Bortezomib treatment activates the terminal UPR.
Figure 4: Bortezomib treatment prevents and ameliorates lupus-like disease in NZB/W F1 mice.
Figure 5: Bortezomib (Bz) treatment ameliorates lupus-like disease in MRL/lpr mice.

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Acknowledgements

We are grateful to U. Appelt for expert cell sorting and M. Wiesener and F. Nimmerjahn for critical reading the manuscript. This work was supported by the Interdisciplinary Center for Clinical Research (project number N2) and the German Research Society (project VO673/31 and Collaborative Research Centers SFB 643; project B3, both to R.E.V.). Parts of this work were funded by an intramural grant from the ELAN fond, a Training Grant GK 592 from the German Research Society and Collaborative Research Centers SFB 423 (project Z2).

Author information

K.N. designed experiments; performed animal studies, flow cytometry, ELISAs, ELISPOTs and quantitative real-time RT-PCR; analyzed data; generated figures and wrote the manuscript. S.M. assisted in performing flow cytometry and animal experiments and participated in discussions. K.M. performed and assisted with the BrdU experiments, provided antibodies and participated in discussions. F.W. performed RNA isolation and cDNA synthesis and participated in discussions. D.M. assisted with the animal studies. K.A. performed all histological analyses. C.W. contributed to the analyses of DC and T cell function. T.H.W. provided crucial ideas, participated in discussions and edited the manuscript. J.R.K. participated in discussions and edited the manuscript. R.A.M. crucially participated in design and analyses of the BrdU labeling experiments, provided antibodies, participated in discussions and edited the manuscript. R.E.V. provided crucial ideas, designed the study and experiments, supervised the study and wrote the manuscript together with K.N.

Correspondence to Reinhard E Voll.

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Competing interests

R.E.V. holds stocks of Millenium Pharmaceuticals, the manufacturer of bortezomib (value of less than $15,000).

K.N., S.M., K.M., R.A.M., D.M., J.R.K. and R.E.V. are inventors listed on a patent application for the use of proteasome inhibitors to deplete plasma cells.

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