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Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan

Manuela Frese-Schaper, Jakob Zbaeren, Mathias Gugger, Marc Monestier and Steffen Frese
J Immunol February 15, 2010, 184 (4) 2175-2182; DOI: https://doi.org/10.4049/jimmunol.0903153
Manuela Frese-Schaper
*Department of Clinical Research, University Hospital Bern;
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Jakob Zbaeren
*Department of Clinical Research, University Hospital Bern;
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Mathias Gugger
†Institute of Pathology, University of Bern, Bern, Switzerland; and
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Marc Monestier
‡Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, PA 19140
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Steffen Frese
*Department of Clinical Research, University Hospital Bern;
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  • FIGURE 1.
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    FIGURE 1.

    Prevention of murine lupus erythematosus by inhibition of topoisomerase I. NZB/W F1 mice were treated from week 13 with 25 mg/kg or 50 mg/kg irinotecan three times per week every fourth week (n = 10, control mice; n = 12, both groups treated with irinotecan). A, Frequency of mice with proteinuria. Each point reflects the frequency of mice with grade 2+ (≥100 mg/dl) proteinuria at the indicated time points. B, Survival of irinotecan-treated groups was significantly better compared with saline-treated groups. p < 0.0001; Kaplan-Meier log-rank test. At week 50/51, half of the groups treated with irinotecan were sacrificed for further analysis. C, Normal development of body weight in irinotecan-treated mice versus decline of body weight in saline-treated controls owing to the onset of the lupus disease. ***p < 0.001; two-way ANOVA.

  • FIGURE 2.
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    FIGURE 2.

    Irinotecan protects NZB/W F1 from the onset of lupus-associated glomerulonephritis. A and C, Representative kidney sections stained with H&E from a control mouse with end-stage lupus nephritis and from 50-wk-old mice that had been treated with either 25 mg/kg or 50 mg/kg irinotecan. The kidney score was assessed in a blinded manner according to the ISN/RPS2003 classification using paraffin sections stained with H&E, methenamine silver, and periodic acid-Schiff reagent as well as frozen sections stained for IgG. B, D, and E, Demonstration of IgG deposits in the kidneys of lupus-prone mice. The score for mesangial and subendothelial immune deposits was determined by the pathologist in a blinded manner. Original magnifications ×40 (A) and ×63 (B).

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    FIGURE 3.

    Induction of ssDNA and impaired renal cell apoptosis in irinotecan-treated mice. A–C, ssDNA was determined on kidney sections using the mAb F7-26. D–F, Apoptosis-induced dsDNA breaks were assessed by TUNEL staining. G, Quantification of dsDNA at a ratio of total DNA. Genomic DNA was isolated from kidneys; total DNA was measured at 260 nm and adjusted to 100 ng/ml. dsDNA was determined using the PicoGreen assay. *p < 0.05; one-way ANOVA. H, Caspase-3 activity was measured in kidney lysates using DEVD-afc as a substrate (original magnification × 63). ***p < 0.001; one-way ANOVA.

  • FIGURE 4.
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    FIGURE 4.

    Recovery from established murine lupus erythematosus after treatment with irinotecan. NZB/W F1 mice with grade 3+ proteinuria (≥300 mg/dl) were treated three times per week for 2 wk with either 50 mg/kg irinotecan or saline. A third group was treated with irinotecan beginning from grade 4+ proteinuria (≥ 2000 mg/dl; n = 10, control mice; n = 12, irinotecan-treated mice [grade 3+]; n = 11, irinotecan treated mice [grade 4+]). Relapsing disease was handled similar to the initial treatment. A, Irinotecan induced a decline of proteinuria within 2 wk after initiation of the treatment. *p < 0.05; **p < 0.01; ***p < 0.001; two-way ANOVA. Data represent mean values ± SEM. B, Kaplan-Meier survival curves showed significantly increased survival of both irinotecan-treated groups compared with saline-treated controls. p < 0.0001; log-rank test.

  • FIGURE 5.
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    FIGURE 5.

    Histologic changes and extent of apoptosis in NZB/W F1 mice treated with established disease. To judge the severity of the disease, kidney sections and lysates of mice (sacrificed 1 wk after completion of saline and 1 and 4 wk after completion of irinotecan treatment) were assessed. A–C, Demonstration of IgG deposits in kidneys of lupus-prone mice. The score for mesangial and subendothelial IgG was assessed in a blinded manner. D and E, The kidney score was determined in a blinded manner using the ISN/RPS2003 classification. F, Caspase-3 activity was measured in kidney lysates using DEVD-afc as a substrate. Original magnifications × 63 (A) and ×40 (D). *p < 0.05; one-way ANOVA.

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    Table I. Immunology of NZB/W F1 mice treated from week 13 with irinotecan compared with saline-treated controls
    Saline25 mg/kg Irinotecan50 mg/kg Irinotecan
    Spleen cell populations
      B220+ cells (%)32.89 ± 3.3122.17 ± 2.32*20.95 ± 3.89***
      IgMlowIgDlow B cells (%)9.79 ± 3.7214.25 ± 4.6511.13 ± 3.59
      IgG-producing B cells (ELISPOTs per 106 cells)5497 ± 38131787 ± 1703**479 ± 602**
      CD4+/CD8+ ratio4.79 ± 2.22.34 ± 0.43**2.09 ± 0.25**
      CD69+ CD4 cells (%)6.01 ± 1.564.03 ± 1.13**3.13 ± 0.77***
      CD11b+ cells (%)1.73 ± 0482.64 ± 1.472.24 ± 0.32
    Neutrophils from peripheral blood (103/mm3)0.40 ± 0.370.42 ± 0.210.34 ± 0.17
    IgG anti-ds DNA (A405–490 nm)2.01 ± 0.672.31 ± 0.501.29 ± 0.63
    Total IgG (mg/ml)9.87 ± 4.8213.99 ± 5.3912.72 ± 6.77
    • Saline-treated control mice were sacrificed when they had reached proteinuria grade 4+ and weight loss >25% calculated from the beginning of the disease (n = 6). The mean age of saline-treated animals was 39 wk. Irinotecan-treated animals were sacrificed at week 50/51 (n = 6, both groups).

    • ↵* p < 0.05; **p < 0.01; ***p < 0.001.

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    Table II. Immunology of NZB/W F1 mice with established lupus nephritis treated with irinotecan compared with saline-treated controls.
    Treatment from Proteinuria Grade 3+ (Time to Sacrifice after Completion of the Treatment)
    1 wk after Saline1 wk after Irinotecan4 wk after Irinotecan
    Spleen cell populations
      B220+ cells (%)32.19 ± 7.3424.04 ± 5.2031.78 ± 6.81
      IgMlowIgDlow B cells (%)20.59 ± 5.9413.67 ± 2.52*23.68 ± 3.77
      IgG-producing B cells (ELISPOTs per 106 cells)12011 ± 59521387 ± 1120**11093 ± 1577
      CD4+/CD8+ ratio5.91 ± 2.983.92 ± 1.346.16 ± 1.88
      CD69+ CD4 cells (%)5.79 ± 3.284.63 ± 1.529.66 ± 1.95*
    Neutrophils from peripheral blood (103/mm3)0.33 ± 0.120.65 ± 0.720.33 ± 0.15
    IgG anti-ds DNA (A405–490 nm)2.17 ± 0.631.68 ± 0.902.37 ± 0.50
    Total IgG (mg/ml)11.72 ± 8.228.62 ± 5.6225.78 ± 10.60*
    • Two groups of NZB/W F1 mice were treated from grade 3+ proteinuria with irinotecan (50 mg/kg, a total of six applications within 2 wk) or saline (10 ml/kg), and sacrificed 1 wk after completion of the treatment. A third group of irinotecan-treated mice was sacrificed 4 wk after the last application.

    • ↵* p < 0.05; **p < 0.001.

    • View popup
    Table III. Comparison of different studies demonstrating survival and remission rates after treatment of established lupus nephritis in NZB/W F1 mice
    Median Survival in Weeks
(Median Time to Death after Onset of Proteinuria in Weeks)
    Grade 3+Grade 4+Grade 3+ and 4+Remission of Proteinuria Grade 3+ (4+) (%)Median Time to Relapse Grade 3+ (4+) in Weeks
    CTX (11)———10a—
    Azathioprine (12)———18a—
    CTX + azathioprine + 
methylprednisolone (14)——440—
    C-reactive protein (16)—46—100—
    CTX + CTLA4Ig and CTX +
CTLA4Ig + α-CD154 (15)———60–80b,c—
    Irinotecan70 (35)76 (39)73 (35)75 (55)b,c9 (12)
    • ↵a Grade of proteinuria before treatment not indicated, for CTX alone at least 5 animals with grade 2+.

    • ↵b Defined as 30 mg/dl of proteinuria or less maintained for at least 3 wk.

    • ↵c Rate of remission owing to the first treatment cycle.

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The Journal of Immunology: 184 (4)
The Journal of Immunology
Vol. 184, Issue 4
15 Feb 2010
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Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan
Manuela Frese-Schaper, Jakob Zbaeren, Mathias Gugger, Marc Monestier, Steffen Frese
The Journal of Immunology February 15, 2010, 184 (4) 2175-2182; DOI: 10.4049/jimmunol.0903153

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Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan
Manuela Frese-Schaper, Jakob Zbaeren, Mathias Gugger, Marc Monestier, Steffen Frese
The Journal of Immunology February 15, 2010, 184 (4) 2175-2182; DOI: 10.4049/jimmunol.0903153
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