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

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.

Reovirus therapy stimulates endoplasmic reticular stress, NOXA induction, and augments bortezomib-mediated apoptosis in multiple myeloma

“…Bortezomib may also have immunosuppressive effects, which could account for some of the activity of this combination in vivo. Bortezomib has been shown to inhibit plasma cells, dendritic cells and the generation of graft-versus-host disease (Sun et al, 2004;Nencioni et al, 2006;Neubert et al, 2008). However, the Reolysin/bortezomib combination displayed potent efficacy in both a human xenograft model in SCID mice and a syngeneic model in immunocompetent mice, suggesting that the therapeutic effects of this combination involves direct tumor cytotoxicity, rather than complete dependence upon an immune response.…”

The Pathogenesis of Lupus Nephritis

“…97 Massive antibody production in plasma cells involves the intracellular proteasome complex for protein processing. The proteasome inhibitor bortezomib was proven to be effective in mouse models of LN, 98,99 but clinical trials with bortezomib in human LN is still pending.…”

Targeted silencing of DNA-specific B cells combined with partial plasma cell depletion displays additive effects on delaying disease onset in lupus-prone mice

“…Bortezomib (Bz), a selective inhibitor of the 26S proteasome, has been approved for the treatment of refractory multiple myeloma and mantle cell lymphoma. When proteasome activity is inhibited defective immunoglobulin chains accumulate, causing overwhelming endoplasmic reticulum stress and terminal unfolded protein response, resulting in apoptotic cell death [13,14]. The same mechanisms also make normal plasma cells, including the long-lived ones, sensitive to proteasome inhibition.…”

“…The same mechanisms also make normal plasma cells, including the long-lived ones, sensitive to proteasome inhibition. The administration of Bz has been shown to reduce autoantibody levels significantly and to prolong survival in Murphy Roths large (MRL)/lpr and New Zealand black (NZB)/New Zealand white (NZW) lupus mice [13]. Proteasome inhibitors are toxic agents, especially after long-term use.…”