Bortezomib Plus Continuous B Cell Depletion Results in Sustained Plasma Cell Depletion and Amelioration of Lupus Nephritis in NZB/W F1 Mice.
Bortezomib Plus Continuous B Cell Depletion Results in Sustained Plasma Cell Depletion and Amelioration of Lupus Nephritis in NZB/W F1 Mice.
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DOI：
10.1371/journal.pone.0135081
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Taddeo A
中科院分区：
文献类型：
--
作者：
Khodadadi L;Cheng Q;Alexander T;Sercan-Alp Ö;Klotsche J;Radbruch A;Hiepe F;Hoyer BF;Taddeo A
长寿命浆细胞（llpc）是一个尚未实现的治疗挑战，针对它们的靶向策略是自身抗体介导的疾病（如系统性红斑狼疮（SLE））的新兴目标。先前的研究表明，浆细胞可以被硼替佐米（Bz）等药物或阻断LFA-1和VLA-4整合素耗尽。然而，由于自身免疫条件下B细胞过度活跃，它们在消耗后迅速再生。因此，我们比较了清除LLPCs的不同疗法与选择性b细胞靶向相结合，以确定在狼疮易发的NZB/W F1小鼠中清除LLPCs并阻止其再生的最有效治疗方法。NZB/W F1小鼠分别用：1)抗cd20, 2)抗cd20 +硼替佐米，3)抗cd20 +抗lfa -1/抗vla4阻断抗体，4)抗cd20 +硼替佐米和抗lfa -1/抗vla4阻断抗体。用流式细胞术和ELISPOT检测治疗7天后小鼠骨髓和脾脏的短寿命和长寿命浆细胞（包括自身反应细胞）。基于这些数据，在另一项实验中，小鼠接受了一个周期的抗cd20 +硼替佐米治疗，然后每10天接受4个周期的抗cd20治疗，并监测其对浆细胞和疾病的影响。骨髓和脾脏中的短命浆细胞被所有靶向浆细胞的治疗方案有效地耗尽。相反，骨髓和脾脏中的LLPCs和抗dsdna分泌浆细胞表现出抗耗尽性，并被硼替佐米加抗cd20强烈降低。硼替佐米对浆细胞的有效消耗加上抗cd20对浆细胞前体B细胞的持续消耗，促进了NZB/W F1小鼠IgG抗dsdna抗体的持续降低，延缓了肾炎的发生，延长了生存期。这些发现表明，硼替佐米联合持续靶向B细胞作为其前体的治疗可以有效地消耗llpc，从而阻止自身反应性llpc的再生，因此可能代表了SLE和其他（自身）抗体介导的疾病的有希望的治疗策略。
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. NZB/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. Short-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. These 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.