Depletion of B cells in murine lupus: Efficacy and resistance
Depletion of B cells in murine lupus: Efficacy and resistance
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DOI：
10.4049/jimmunol.179.5.3351
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发表时间：
2007-09-01
影响因子：
4.4
通讯作者：
Shlomchik, Mark J.
中科院分区：
文献类型：
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作者：
Ahuja, Anupama;Shupe, Jonathan;Shlomchik, Mark J.
在小鼠中，B细胞的基因缺失强烈抑制了全身自身免疫，为耗尽B细胞治疗自身免疫提供了理论基础。事实上，利妥昔单抗去除B细胞已被批准用于类风湿关节炎患者，系统性红斑狼疮的临床试验正在进行中。然而，关于B细胞耗竭的机制、病理效应和程度的基本问题在人类中并不容易研究。为了更好地了解B细胞耗尽如何影响自身免疫，我们在自身免疫倾向的MRL/MPJ-Fas(LPR)(MRL/LPR)背景下培育了一只在B细胞上表达人CD20的转基因小鼠。使用大剂量的小鼠抗人CD20单抗，我们能够显著耗尽B细胞，这反过来又显著改善了临床和组织学疾病，以及抗核抗体和血清自身抗体水平。然而，我们也发现，与非自身免疫倾向株相比，自身免疫倾向株中的B细胞很难耗尽。多种抗CD20抗体也是如此，包括一种新的抗鼠CD20抗体，以及几种不同的自身免疫倾向株。因此，虽然成功的B细胞去除是狼疮的一种有希望的治疗方法，但至少有一些患者可能会抵抗这种治疗，因为这是自身免疫状况本身的副产品。
In mice, genetic deletion of B cells strongly suppresses systemic autoimmunity, providing a rationale for depleting B cells to treat autoimmunity. In fact, B cell depletion with rituximab is approved for rhematoid arthritis patients, and clinical trials are underway for systemic lupus erythematosus. Yet, basic questions concerning mechanism, pathologic effect, and extent of B cell depletion cannot be easily studied in humans. To better understand how B cell depletion affects autoimmunity, we have generated a transgenic mouse expressing human CD20 on B cells in an autoimmune-prone MRL/MpJ-Fas(lpr) (MRL/lpr) background. Using high doses of a murine anti-human CD20 mAb, we were able to achieve significant depletion of B cells, which in turn markedly ameliorated clinical and histologic disease as well as antinuclear Ab and serum autoantibody levels. However, we also found that B cells were quite refractory to depletion in autoimmune-prone strains compared with non-autoimmune-prone strains. This was true with multiple anti-CD20 Abs, including a new anti-mouse CD20 Ab, and in several different autoimmune-prone strains. Thus, whereas successful B cell depletion is a promising therapy for lupus, at least some patients might be resistant to the therapy as a byproduct of the autoimmune condition itself.