Neubert K et al. (2008) The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 14: 748–755

Long-lived plasma cells, which produce autoantibodies in diseases such as systemic lupus erythematosus (SLE), are an as yet unexplored therapeutic target in such antibody-mediated disorders. Bortezomib (a proteasome inhibitor) has recently been approved for treatment of relapsed multiple myeloma, a plasma cell neoplasia, owing to the sensitivity of immunoglobulin-synthesizing myeloma cells towards proteasome inhibitors. Neubert and colleagues hypothesized that bortezomib could also target autoantibody-producing plasma cells implicated in the pathogenesis of SLE, and investigated the outcomes of proteasome inhibition in mice with lupus-like disease.

The researchers found that, for the depletion of total and long-lived plasma cells in mouse bone marrow, bortezomib was more efficient and specific than the standard SLE treatments dexamethasone and cyclophosphamide. A marked decrease in plasma cells (>60% in spleens, >95% in bone marrow) was observed within 48 h of bortezomib treatment, indicating that the proteasome inhibitor acts directly on these cells. Bortezomib treatment also significantly decreased double-stranded-DNA-specific autoantibody production after 7 days, whereas the standard treatment had no effect. Mice treated with bortezomib remained healthy and survived much longer than control mice treated with phosphate buffer solution only.

Neubert et al. conclude that elimination of autoantibody-producing plasma cells by proteasome inhibitors might represent a new treatment strategy for antibody-mediated diseases, and warrant further careful clinical studies.