Low-Dose Irinotecan Improves Advanced Lupus Nephritis in Mice Potentially by Changing DNA Relaxation and Anti-Double-Stranded DNA Binding
Low-Dose Irinotecan Improves Advanced Lupus Nephritis in Mice Potentially by Changing DNA Relaxation and Anti-Double-Stranded DNA Binding
复制标题
DOI：
10.1002/art.38665
复制
发表时间：
2014-08-01
影响因子：
13.3
通讯作者：
Frese, Steffen
中科院分区：
文献类型：
--
作者：
Frese-Schaper, Manuela;Keil, Andreas;Frese, Steffen
目标。尽管系统性红斑狼疮(SLE)的治疗取得了明显进展，但许多患者仍存在难治性狼疮性肾炎，需要新的治疗策略。本研究旨在确定减少剂量的拓扑异构酶I(Topo I)抑制剂伊立替康对(NZB X NZW)F1(NZB/NZW)小鼠系统性红斑狼疮(SLE)的抑制作用，并探讨伊立替康影响SLEs的可能机制。NZB/NZW小鼠从24周龄开始服用小剂量伊立替康，或建立肾小球肾炎，定义为>；=3+级蛋白尿。用酶联免疫吸附试验(ELISA)检测抗双链DNA(抗dsDNA)抗体的结合力，用凝胶电泳法观察DNA松弛情况。显著减少伊立替康剂量可改善狼疮性肾炎并延长NZB/NZW小鼠的存活时间。成功用于治疗已确诊的小鼠狼疮性肾炎的最低剂量比通常用于人类化疗的剂量低50倍。作为一种机制，小剂量伊立替康降低了B细胞的活性。然而，伊立替康治疗的小鼠的B细胞活性水平与同龄BALB/c小鼠相似，表明伊立替康没有诱导明显的免疫抑制。此外，与Topo I孵育dsDNA可增加鼠和人抗dsDNA抗体的结合，首次表明松弛的DNA对抗dsDNA抗体结合更敏感。这种作用可被Topo I抑制剂喜树碱逆转。我们的发现表明，Topo I抑制可能是一种新的靶向治疗SLE的方法。
Objective. Despite clear advances in the treatment of systemic lupus erythematosus (SLE), many patients still present with refractory lupus nephritis, requiring new treatment strategies for this disease. This study was undertaken to determine whether reduced doses of the topoisomerase I (topo I) inhibitor irinotecan, which is known as a chemotherapeutic agent, suppress SLE in (NZB x NZW)F1 (NZB/NZW) mice, and to evaluate the potential mechanism by which irinotecan influences the course of SLE.Methods. NZB/NZW mice were treated with low-dose irinotecan beginning at either 24 weeks of age or established glomerulonephritis, defined as proteinuria of grade >= 3+. Binding of anti-double-stranded DNA (anti-dsDNA) antibodies was measured by enzyme-linked immunosorbent assay (ELISA), and DNA relaxation was visualized by gel electrophoresis.Results. Significantly reduced irinotecan doses improved lupus nephritis and prolonged survival in NZB/NZW mice. The lowest dose successfully used for the treatment of established murine lupus nephritis was >50 times lower than the dose usually used for chemotherapy in humans. As a mechanism, low-dose irinotecan reduced B cell activity. However, the levels of B cell activity in irinotecan-treated mice were similar to those in BALB/c mice of the same age, suggesting that irinotecan did not induce clear immunosuppression. In addition, incubation of dsDNA with topo I increased binding of murine and human anti-dsDNA antibodies, showing for the first time that relaxed DNA is more susceptible to anti-dsDNA antibody binding. This effect was reversed by addition of the topo I inhibitor camptothecin.Conclusion. Our findings indicate that topo I inhibition may be a novel and targeted therapy for SLE.