Abstract
Long-lived plasma cells (LLPCs) are an unmet therapeutic challenge, and developing strategies for their targeting is an emerging goal of autoantibody-mediated diseases such as systemic lupus erythematosus (SLE). It was previously shown that plasma cells can be depleted by agents such as bortezomib (Bz) or by blocking LFA-1 and VLA-4 integrins. However, they regenerate quickly after depletion due to B cell hyperactivity in autoimmune conditions. Therefore, we compared different therapies for the elimination of LLPCs combined with selective B-cell targeting in order to identify the most effective treatment to eliminate LLPCs and prevent their regeneration in lupus-prone NZB/W F1 mice.MethodsNZB/W F1 mice were treated with: 1) anti-CD20, 2) anti-CD20 plus bortezomib, 3) anti-CD20 plus anti-LFA-1/anti-VLA-4 blocking antibodies, 4) anti-CD20 plus bortezomib and anti-LFA-1/anti-VLA4 blocking antibodies. Short- and long-lived plasma cells including autoreactive cells in the bone marrow and spleen were enumerated by flow cytometry and ELISPOT seven days after treatment. Based on these data in another experiment, mice received one cycle of anti-CD20 plus bortezomib followed by four cycles of anti-CD20 therapy every 10 days and were monitored for its effect on plasma cells and disease.ResultsShort-lived plasma cells in bone marrow and spleen were efficiently depleted by all regimens targeting plasma cells. Conversely, LLPCs and anti-dsDNA-secreting plasma cells in bone marrow and spleen showed resistance to depletion and were strongly reduced by bortezomib plus anti-CD20. The effective depletion of plasma cells by bortezomib complemented by the continuous depletion of their precursor B cells using anti-CD20 promoted the persistent reduction of IgG anti-dsDNA antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice.ConclusionsThese findings suggest that the effective depletion of LLPCs using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, thus, might represent a promising treatment strategy for SLE and other (auto)antibody-mediated diseases.
Highlights
Aberrant production of autoantibodies against diverse nuclear antigens is a hallmark of systemic lupus erythematosus (SLE) [1, 2]
Persistent reduction of IgG anti-double-stranded DNA (dsDNA) antibodies, delayed nephritis and prolonged survival in NZB/W F1 mice. These findings suggest that the effective depletion of long-lived plasma cells (LLPCs) using bortezomib in combination with a therapy that continuously targeting B cells as their precursors may prevent the regeneration of autoreactive LLPCs and, might represent a promising treatment strategy for SLE and otherantibody-mediated diseases
Mice were divided into five groups and treated with a) vehicle, b) anti-mouse CD20 antibody, c) anti-mouse CD20 plus anti-leukocyte function-associated antigen-1 (LFA-1)/anti-very late antigen-4 (VLA-4) blocking antibodies, d) anti-mouse CD20 combined with bortezomib, or e) anti-mouse CD20 together with bortezomib and antiLFA-1/anti-VLA-4 antibodies
Summary
Aberrant production of autoantibodies against diverse nuclear antigens is a hallmark of systemic lupus erythematosus (SLE) [1, 2]. In 1997 [3] and 1998 [4], two groups independently showed that persistent antibody titers are caused by long-lived plasma cells (LLPCs). While immunosuppressive therapy and anti-CD20 monoclonal antibody (mAb) therapy can deplete short-lived plasmablasts and plasma cells (SLPCs), LLPCs are resistant to immunosuppressive drugs [5, 7] and B-cell depletion (BCD) therapies [8]. These findings indicate that targeting pathogenic LLPCs could be promising for the treatment of SLE patients
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