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

Nature Medicine volume 14, pages 748–755 (2008)Cite this article

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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References

  1. Lipsky, P.E. Systemic lupus erythematosus: an autoimmune disease of B cell hyperactivity. Nat. Immunol. 2, 764–766 (2001).

    Article  CAS  Google Scholar 

  2. Mills, J.A. Systemic lupus erythematosus. N. Engl. J. Med. 330, 1871–1879 (1994).

    Article  CAS  Google Scholar 

  3. Manz, R.A. & Radbruch, A. Plasma cells for a lifetime? Eur. J. Immunol. 32, 923–927 (2002).

    Article  CAS  Google Scholar 

  4. Miller, J.J., III & Cole, L.J. Resistance of long-lived lymphocytes and plasma cells in rat lymph nodes to treatment with prednisone, cyclophosphamide, 6 mercaptopurine and actinomycin D. J. Exp. Med. 126, 109–125 (1967).

    Article  CAS  Google Scholar 

  5. Slifka, M.K. & Ahmed, R. Long-lived plasma cells: a mechanism for maintaining persistent antibody production. Curr. Opin. Immunol. 10, 252–258 (1998).

    Article  CAS  Google Scholar 

  6. Ang, H.A., Apperley, J.F. & Ward, K.N. Persistence of antibody to human parvovirus B19 after allogeneic bone marrow transplantation: role of prior recipient immunity. Blood 89, 4646–4651 (1997).

    CAS  PubMed  Google Scholar 

  7. van Tol, M.J. et al. The origin of IgG production and homogeneous IgG components after allogeneic bone marrow transplantation. Blood 87, 818–826 (1996).

    CAS  PubMed  Google Scholar 

  8. Theofilopoulos, A.N. & Dixon, F.J. Murine models of systemic lupus erythematosus. Adv. Immunol. 37, 269–390 (1985).

    Article  CAS  Google Scholar 

  9. Hoyer, B.F. et al. Short-lived plasmablasts and long-lived plasma cells contribute to chronic humoral autoimmunity in NZB/W mice. J. Exp. Med. 199, 1577–1584 (2004).

    Article  CAS  Google Scholar 

  10. Manz, R.A., Hauser, A.E., Hiepe, F. & Radbruch, A. Maintenance of serum antibody levels. Annu. Rev. Immunol. 23, 367–386 (2005).

    Article  CAS  Google Scholar 

  11. Adams, J. The proteasome: a suitable antineoplastic target. Nat. Rev. Cancer 4, 349–360 (2004).

    Article  CAS  Google Scholar 

  12. Hideshima, T., Richardson, P.G. & Anderson, K.C. Targeting proteasome inhibition in hematologic malignancies. Rev. Clin. Exp. Hematol. 7, 191–204 (2003).

    CAS  PubMed  Google Scholar 

  13. Rajkumar, S.V., Richardson, P.G., Hideshima, T. & Anderson, K.C. Proteasome inhibition as a novel therapeutic target in human cancer. J. Clin. Oncol. 23, 630–639 (2005).

    Article  CAS  Google Scholar 

  14. Meister, S. et al. Extensive immunoglobulin production sensitizes myeloma cells for proteasome inhibition. Cancer Res. 67, 1783–1792 (2007).

    Article  CAS  Google Scholar 

  15. Obeng, E.A. et al. Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells. Blood 107, 4907–4916 (2006).

    Article  CAS  Google Scholar 

  16. Hibi, T. & Dosch, H.M. Limiting dilution analysis of the B cell compartment in human bone marrow. Eur. J. Immunol. 16, 139–145 (1986).

    Article  CAS  Google Scholar 

  17. Lefkowith, J.B. & Gilkeson, G.S. Nephritogenic autoantibodies in lupus: current concepts and continuing controversies. Arthritis Rheum. 39, 894–903 (1996).

    Article  CAS  Google Scholar 

  18. Hahn, B.H. Antibodies to DNA. N. Engl. J. Med. 338, 1359–1368 (1998).

    Article  CAS  Google Scholar 

  19. Manz, R.A., Thiel, A. & Radbruch, A. Lifetime of plasma cells in the bone marrow. Nature 388, 133–134 (1997).

    Article  CAS  Google Scholar 

  20. Radbruch, A. et al. Competence and competition: the challenge pf becoming a long-lived plasma cell. Nat. Rev. Immunol. 6, 741–750 (2006).

    Article  CAS  Google Scholar 

  21. Nencioni, A. et al. Proteasome inhibitor bortezomib modulates TLR4-induced dendritic cell activation. Blood 108, 551–558 (2006).

    Article  CAS  Google Scholar 

  22. Straube, C. et al. Bortezomib significantly impairs the immunostimulatory capacity of human myeloid blood dendritic cells. Leukemia 21, 1464–1471 (2007).

    Article  CAS  Google Scholar 

  23. Oyadomari, S. & Mori, M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ. 11, 381–389 (2004).

    Article  CAS  Google Scholar 

  24. Moran, S.T. et al. Synergism between NF-κB1/p50 and Notch2 during the development of marginal zone B lymphocytes. J. Immunol. 179, 195–200 (2007).

    Article  CAS  Google Scholar 

  25. Sasaki, Y. et al. Canonical NF-κB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 24, 729–739 (2006).

    Article  CAS  Google Scholar 

  26. Maseda, D., Meister, S., Neubert, K., Herrmann, M. & Voll, R.E. Proteasome inhibition drastically but reversibly impairs murine lymphocyte development. Cell Death Differ. 15, 600–612 (2008).

    Article  CAS  Google Scholar 

  27. Schubert, U. et al. Rapid degradation of a large fraction of newly synthesized proteins by proteasomes. Nature 404, 770–774 (2000).

    Article  CAS  Google Scholar 

  28. Gass, J.N., Gifford, N.M. & Brewer, J.W. Activation of an unfolded protein response during differentiation of antibody-secreting B cells. J. Biol. Chem. 277, 49047–49054 (2002).

    Article  CAS  Google Scholar 

  29. Iwakoshi, N.N. et al. Plasma cell differentiation and the unfolded protein response intersect at the transcription factor XBP-1. Nat. Immunol. 4, 321–329 (2003).

    Article  CAS  Google Scholar 

  30. Kaufman, R.J. Stress signaling from the lumen of the endoplasmic reticulum: coordination of gene transcriptional and translational controls. Genes Dev. 13, 1211–1233 (1999).

    Article  CAS  Google Scholar 

  31. Patil, C. & Walter, P. Intracellular signaling from the endoplasmic reticulum to the nucleus: the unfolded protein response in yeast and mammals. Curr. Opin. Cell Biol. 13, 349–355 (2001).

    Article  CAS  Google Scholar 

  32. Reimold, A.M. et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature 412, 300–307 (2001).

    Article  CAS  Google Scholar 

  33. van Anken, E. et al. Sequential waves of functionally related proteins are expressed when B cells prepare for antibody secretion. Immunity 18, 243–253 (2003).

    Article  CAS  Google Scholar 

  34. Wiertz, E.J. et al. Sec61-mediated transfer of a membrane protein from the endoplasmic reticulum to the proteasome for destruction. Nature 384, 432–438 (1996).

    Article  CAS  Google Scholar 

  35. Kim, R., Emi, M., Tanabe, K. & Murakami, S. Role of the unfolded protein response in cell death. Apoptosis 11, 5–13 (2006).

    Article  CAS  Google Scholar 

  36. Nawrocki, S.T. et al. Bortezomib inhibits PKR-like endoplasmic reticulum (ER) kinase and induces apoptosis via ER stress in human pancreatic cancer cells. Cancer Res. 65, 11510–11519 (2005).

    Article  CAS  Google Scholar 

  37. Nawrocki, S.T. et al. Bortezomib sensitizes pancreatic cancer cells to endoplasmic reticulum stress-mediated apoptosis. Cancer Res. 65, 11658–11666 (2005).

    Article  CAS  Google Scholar 

  38. Schaumann, D.H., Tuischer, J., Ebell, W., Manz, R.A. & Lauster, R. VCAM-1–positive stromal cells from human bone marrow producing cytokines for B lineage progenitors and for plasma cells: SDF-1, flt3L and BAFF. Mol. Immunol. 44, 1606–1612 (2007).

    Article  CAS  Google Scholar 

  39. Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B.I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004).

    Article  CAS  Google Scholar 

  40. Klinman, D.M. & Steinberg, A.D. Inquiry into murine and human lupus. Immunol. Rev. 144, 157–193 (1995).

    Article  CAS  Google Scholar 

  41. Winfield, J.B., Faiferman, I. & Koffler, D. Avidity of anti-DNA antibodies in serum and IgG glomerular eluates from patients with systemic lupus erythematosus. Association of high avidity antinative DNA antibody with glomerulonephritis. J. Clin. Invest. 59, 90–96 (1977).

    Article  CAS  Google Scholar 

  42. Cambridge, G. et al. B cell depletion therapy in systemic lupus erythematosus: effect on autoantibody and antimicrobial antibody profiles. Arthritis Rheum. 54, 3612–3622 (2006).

    Article  CAS  Google Scholar 

  43. Sfikakis, P.P. et al. Remission of proliferative lupus nephritis following B cell depletion therapy is preceded by down-regulation of the T cell costimulatory molecule CD40 ligand: an open-label trial. Arthritis Rheum. 52, 501–513 (2005).

    Article  CAS  Google Scholar 

  44. Leandro, M.J., Edwards, J.C., Cambridge, G., Ehrenstein, M.R. & Isenberg, D.A. An open study of B lymphocyte depletion in systemic lupus erythematosus. Arthritis Rheum. 46, 2673–2677 (2002).

    Article  Google Scholar 

  45. Emery, P. et al. The efficacy and safety of rituximab in patients with active rheumatoid arthritis despite methotrexate treatment: results of a phase IIB randomized, double-blind, placebo-controlled, dose-ranging trial. Arthritis Rheum. 54, 1390–1400 (2006).

    Article  CAS  Google Scholar 

  46. Looney, R.J. et al. B cell depletion as a novel treatment for systemic lupus erythematosus: a phase I/II dose-escalation trial of rituximab. Arthritis Rheum. 50, 2580–2589 (2004).

    Article  CAS  Google Scholar 

  47. Medina, F., Segundo, C., Campos-Caro, A., Gonzalez-Garcia, I. & Brieva, J.A. The heterogeneity shown by human plasma cells from tonsil, blood, and bone marrow reveals graded stages of increasing maturity, but local profiles of adhesion molecule expression. Blood 99, 2154–2161 (2002).

    Article  CAS  Google Scholar 

  48. Benner, R., Van Oudenaren, A. & Koch, G. Induction of antibody formation in mouse bone marrow. in Immunological Methods Vol. II (eds. Pernis, B. & Lefkovits, I.) 247–262 (Academic Press, New York, 1981).

    Chapter  Google Scholar 

  49. Wellmann, U., Letz, M., Schneider, A., Amann, K. & Winkler, T.H. An Ig μ-heavy chain transgene inhibits systemic lupus erythematosus immunopathology in autoimmune (NZB x NZW)F1 mice. Int. Immunol. 13, 1461–1469 (2001).

    Article  CAS  Google Scholar 

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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).

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Authors and Affiliations

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

    Kirsten Neubert, Silke Meister, Damian Maseda & Reinhard E Voll

  2. Department for Humoral Immunology, German Arthritis Research Center, Schumannstrasse 21/22, Berlin, 10117, Germany

    Katrin Moser & Rudolf A Manz

  3. Department Biology, Hematopoiesis Unit, University of Erlangen-Nuremberg, Glückstrasse 6, Erlangen, 91054, Germany

    Florian Weisel & Thomas H Winkler

  4. Institute for Pathology, University of Erlangen-Nuremberg, Ramistrasse 100, Erlangen, 91054, Germany

    Kerstin Amann

  5. Department of Dermatology, University Hospital Erlangen, Hartmannstrasse 14, 91054, Erlangen, Germany

    Carsten Wiethe

  6. Department of Internal Medicine 3 and Institute of Clinical Immunology, University of Erlangen-Nuremberg, Krankenhausstrasse 12, Erlangen, 91054, Germany

    Joachim R Kalden & Reinhard E Voll

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Contributions

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.

Corresponding author

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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Neubert, K., Meister, S., Moser, K. et al. The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 14, 748–755 (2008). https://doi.org/10.1038/nm1763

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