Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells
Correction(s) for this article
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Erratum: Beneficial effect of novel proteasome inhibitors in murine lupus via dual inhibition of type I interferon and autoantibody-secreting cells
- H. Travis Ichikawa,
- Thomas Conley,
- Tony Muchamuel,
- Jing Jiang,
- Susan Lee,
- Teresa Owen,
- Jennifer Barnard,
- Sarah Nevarez,
- Bruce I. Goldman,
- Christopher J. Kirk,
- R. John Looney,
- Jennifer H. Anolik,
- Volume 64Issue 3Arthritis & Rheumatism
- pages: 939-939
- First Published online: February 28, 2012
H. Travis Ichikawa
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorThomas Conley
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorTony Muchamuel
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorJing Jiang
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorSusan Lee
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorTeresa Owen
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorJennifer Barnard
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorSarah Nevarez
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorBruce I. Goldman
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorChristopher J. Kirk
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorR. John Looney
University of Rochester Medical Center, Rochester, New York
Dr. Looney has received consulting fees, speaking fees, and/or honoraria from Onyx Pharmaceuticals (less than $10,000).
Search for more papers by this authorCorresponding Author
Jennifer H. Anolik
University of Rochester Medical Center, Rochester, New York
Dr. Anolik has received consulting fees and/or honoraria from Onyx Pharmaceuticals, Amgen, MedImmune, Pfizer, UCB, Genentech, and Roche (less than $10,000 each).
University of Rochester School of Medicine, Box 695, 601 Elmwood Avenue, Rochester, NY 14642Search for more papers by this authorH. Travis Ichikawa
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorThomas Conley
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorTony Muchamuel
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorJing Jiang
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorSusan Lee
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorTeresa Owen
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorJennifer Barnard
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorSarah Nevarez
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorBruce I. Goldman
University of Rochester Medical Center, Rochester, New York
Search for more papers by this authorChristopher J. Kirk
Onyx Pharmaceuticals, South San Francisco, California
Mr. Muchamuel, Dr. Jiang, Ms Lee, and Dr. Kirk own stock or stock options in Onyx Pharmaceuticals.
Search for more papers by this authorR. John Looney
University of Rochester Medical Center, Rochester, New York
Dr. Looney has received consulting fees, speaking fees, and/or honoraria from Onyx Pharmaceuticals (less than $10,000).
Search for more papers by this authorCorresponding Author
Jennifer H. Anolik
University of Rochester Medical Center, Rochester, New York
Dr. Anolik has received consulting fees and/or honoraria from Onyx Pharmaceuticals, Amgen, MedImmune, Pfizer, UCB, Genentech, and Roche (less than $10,000 each).
University of Rochester School of Medicine, Box 695, 601 Elmwood Avenue, Rochester, NY 14642Search for more papers by this authorAbstract
Objective
To investigate the hypothesis that proteasome inhibition may have potential in the treatment of SLE, by targeting plasmacytoid dendritic cells (PDCs) and plasma cells, both of which are critical in disease pathogenesis.
Methods
Lupus-prone mice were treated with the nonselective proteasome inhibitors carfilzomib and bortezomib, the immunoproteasome inhibitor ONX 0914, or vehicle control. Tissue was harvested and analyzed by flow cytometry using standard markers. Nephritis was monitored by evaluation for proteinuria and by histologic analysis of kidneys. Serum anti–double-stranded DNA (anti-dsDNA) levels were measured by enzyme-linked immunosorbent assay (ELISA), and total IgG and dsDNA antibody-secreting cells (ASCs) by enzyme-linked immunospot assay. Human peripheral blood mononuclear cells or mouse bone marrow cells were incubated with Toll-like receptor (TLR) agonists and proteasome inhibitors, and interferon-α (IFNα) levels were measured by ELISA and flow cytometry.
Results
Early treatment of lupus-prone mice with the dual-targeting proteasome inhibitors carfilzomib or bortezomib or the immunoproteasome-specific inhibitor ONX 0914 prevented disease progression, and treatment of mice with established disease dramatically abrogated nephritis. Treatment had profound effects on plasma cells, with greater reductions in autoreactive than in total IgG ASCs, an effect that became more pronounced with prolonged treatment and was reflected in decreasing serum autoantibody levels. Notably, proteasome inhibition efficiently suppressed production of IFNα by TLR-activated PDCs in vitro and in vivo, an effect mediated by inhibition of both PDC survival and PDC function.
Conclusion
Inhibition of the immunoproteasome is equally efficacious as dual targeting agents in preventing lupus disease progression by targeting 2 critical pathways in disease pathogenesis, type I IFN activation and autoantibody production by plasma cells.
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