Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan.
Suppression of lupus nephritis and skin lesions in MRL/lpr mice by administration of the topoisomerase I inhibitor irinotecan.
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DOI：
10.1186/s13075-016-1144-5
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发表时间：
2016-10-22
影响因子：
4.9
通讯作者：
Frese S
中科院分区：
文献类型：
--
作者：
Keil A;Hall SR;Körner M;Herrmann M;Schmid RA;Frese S
由于系统性红斑狼疮（SLE）发病的确切机制尚不清楚，迄今为止除了免疫抑制外，尚无靶向治疗方法。我们最近证明，极低浓度的拓扑异构酶I （topo I）抑制剂伊立替康可以逆转NZB/NZW小鼠的狼疮性肾炎。虽然没有深刻的免疫抑制，但我们认为DNA松弛和抗双链DNA抗体结合的变化是潜在的机制。为了排除这些影响仅限于NZB/NZW小鼠，伊立替康被用于一种遗传上不同的狼疮易感小鼠。MRL/lpr小鼠从8周龄开始接受高剂量和低剂量伊立替康治疗。每四周重复治疗一次。在体外，用重组topo I放松DNA，用酶联免疫吸附法检测抗dsdna抗体结合的改变。在MRL/lpr小鼠中，高剂量和低剂量伊立替康均可预防蛋白尿并延长生存期。此外，两种浓度的伊立替康在18周龄时显著改善了皮肤的组织病理学。而只有高剂量伊立替康减少质母细胞和双阴性T细胞的数量，IgG分泌细胞和抗dsdna IgG未见变化。在体外，topo I对DNA的松弛作用增加了MRL/lpr小鼠血浆中抗dsdna IgG的结合，但没有增加抗dsdna IgM的结合。在另一种遗传上不同的狼疮易感小鼠中，topo I抑制的有益作用强烈暗示伊立替康是人类狼疮的一种新的治疗选择。
Since the precise mechanism for the pathogenesis of systemic lupus erythematosus (SLE) is unknown, no targeted therapies in addition to immunosuppression are available so far. We recently demonstrated that administration of the topoisomerase I (topo I) inhibitor irinotecan at extremely low concentrations reversed established lupus nephritis in NZB/NZW mice. While profound immunosuppression was absent, we proposed changes in DNA relaxation and anti-double-stranded (ds)DNA antibody binding as the underlying mechanism. To exclude that these effects were restricted to NZB/NZW mice, irinotecan was used in a genetically different strain of lupus-prone mice. MRL/lpr mice were treated with high- and low-dose irinotecan beginning at 8 weeks of age. Treatment was repeated every fourth week. In vitro, DNA was relaxed by recombinant topo I, and altered anti-dsDNA antibody binding was measured by enzyme-linked immunosorbent assay. Administration of both high- and low-dose irinotecan prevented proteinuria and prolonged survival in MRL/lpr mice. Moreover, both concentrations of irinotecan significantly improved histopathology of the skin at 18 weeks of age. While only high-dose irinotecan diminished the numbers of plasmablasts and double-negative T cells, no changes in IgG-secreting cells or anti-dsDNA IgG were observed. In vitro, relaxation of DNA by topo I increased the binding of anti-dsDNA IgG but not the binding of anti-dsDNA IgM derived from the plasma of MRL/lpr mice. The beneficial effects of topo I inhibition in a second, genetically different strain of lupus-prone mice strongly implicate irinotecan as a new therapeutic option for human SLE.
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影响因子：
5.4
作者：
Johnson, Angela C.;Davison, Laura M.;Giltiay, Natalia V.;Vareechon, Chairut;Li, Xiaoxia;Jorgensen, Trine N.
通讯作者：
Jorgensen, Trine N.
影响因子：
4.7
作者：
Hahn, Bevra H.;McMahon, Maureen A.;Wilkinson, Alan;Wallace, W. Dean;Daikh, David I.;Fitzgerald, John D.;Karpouzas, George A.;Merrill, Joan T.;Wallace, Daniel J.;Yazdany, Jinoos;Ramsey-Goldman, Rosalind;Singh, Karandeep;Khalighi, Mazdak;Choi, Soo-In;Gogia, Maneesh;Kafaja, Suzanne;Kamgar, Mohammad;Lau, Christine;Martin, William J.;Parikh, Sefali;Peng, Justin;Rastogi, Anjay;Chen, Weiling;Grossman, Jennifer M.
通讯作者：
Grossman, Jennifer M.
DOI：
10.2215/cjn.00170108
发表时间：
2008-05-01
影响因子：
9.8
作者：
Clark, William F.;Sontrop, Jessica M.
通讯作者：
Sontrop, Jessica M.
影响因子：
13.3
作者：
Frese-Schaper, Manuela;Keil, Andreas;Frese, Steffen
通讯作者：
Frese, Steffen
影响因子：
82.9
作者：
Barber, DF;Bartolomé, A;Carrera, AC
通讯作者：
Carrera, AC